PICK1

Existing Annotations Review

GO Term	Evidence	Action	Reason
GO:0043113 receptor clustering	IBA GO_REF:0000033	ACCEPT	Summary: Receptor clustering is supported by PICK1 PDZ/BAR-dependent organization of synaptic receptor complexes. Reason: receptor clustering is supported as part of PICK1 PDZ/BAR scaffold, membrane-remodeling, or synaptic receptor-trafficking function. Supporting Evidence: file:human/PICK1/PICK1-deep-research-falcon.md Across the recent literature, PICK1’s primary molecular role is best described as a PDZ/BAR scaffold that regulates the trafficking and surface availability of membrane proteins—especially AMPA-type glutamate receptors—by coordinating protein complex assembly with membrane remodeling and endocytic/recycling processes file:human/PICK1/PICK1-deep-research-falcon.md PDZ domain (protein interaction module): In AMPAR biology, authoritative review evidence states that the GluA2 C-terminus contains a PDZ ligand that binds directly to PICK1 (and GRIP1), and that PICK1 binds GluA2 via its PDZ domain
GO:0006886 intracellular protein transport	IBA GO_REF:0000033	ACCEPT	Summary: Intracellular protein transport is central to PICK1 regulation of AMPAR and other membrane-protein trafficking. Reason: intracellular protein transport is supported as part of PICK1 PDZ/BAR scaffold, membrane-remodeling, or synaptic receptor-trafficking function. Supporting Evidence: file:human/PICK1/PICK1-deep-research-falcon.md Across the recent literature, PICK1’s primary molecular role is best described as a PDZ/BAR scaffold that regulates the trafficking and surface availability of membrane proteins—especially AMPA-type glutamate receptors—by coordinating protein complex assembly with membrane remodeling and endocytic/recycling processes
GO:0043005 neuron projection	IBA GO_REF:0000033	ACCEPT	Summary: Neuron projection localization is consistent with PICK1 function in pre- and postsynaptic neuronal compartments. Reason: neuron projection is supported as part of PICK1 PDZ/BAR scaffold, membrane-remodeling, or synaptic receptor-trafficking function. Supporting Evidence: file:human/PICK1/PICK1-deep-research-falcon.md PICK1 is described as enriched in brain and localized to pre- and postsynaptic compartments, consistent with its role in regulating synaptic receptor trafficking
GO:0005543 phospholipid binding	IBA GO_REF:0000033	ACCEPT	Summary: Phospholipid binding is supported by the BAR/N-BAR membrane-binding module. Reason: phospholipid binding is supported as part of PICK1 PDZ/BAR scaffold, membrane-remodeling, or synaptic receptor-trafficking function. Supporting Evidence: file:human/PICK1/PICK1-deep-research-falcon.md BAR / N‑BAR domain (membrane remodeling module): BAR domains are classically crescent-shaped, lipid-binding modules involved in membrane curvature during trafficking. file:human/PICK1/PICK1-deep-research-falcon.md PICK1 is a dual-domain scaffolding/adaptor protein that couples (i) PDZ-domain–mediated binding to C-terminal motifs on cargo proteins with (ii) BAR/N‑BAR–mediated lipid/membrane binding and remodeling, enabling regulation of membrane protein trafficking and compartmentalization
GO:0008021 synaptic vesicle	IBA GO_REF:0000033	ACCEPT	Summary: Synaptic vesicle localization is consistent with synaptic trafficking functions of PICK1. Reason: synaptic vesicle is supported as part of PICK1 PDZ/BAR scaffold, membrane-remodeling, or synaptic receptor-trafficking function. Supporting Evidence: file:human/PICK1/PICK1-deep-research-falcon.md PICK1 is described as enriched in brain and localized to pre- and postsynaptic compartments, consistent with its role in regulating synaptic receptor trafficking
GO:0014069 postsynaptic density	IBA GO_REF:0000033	ACCEPT	Summary: Postsynaptic density localization is supported by PICK1 action at postsynaptic AMPAR complexes. Reason: postsynaptic density is supported as part of PICK1 PDZ/BAR scaffold, membrane-remodeling, or synaptic receptor-trafficking function. Supporting Evidence: file:human/PICK1/PICK1-deep-research-falcon.md PICK1 is described as enriched in brain and localized to pre- and postsynaptic compartments, consistent with its role in regulating synaptic receptor trafficking file:human/PICK1/PICK1-deep-research-falcon.md Across the recent literature, PICK1’s primary molecular role is best described as a PDZ/BAR scaffold that regulates the trafficking and surface availability of membrane proteins—especially AMPA-type glutamate receptors—by coordinating protein complex assembly with membrane remodeling and endocytic/recycling processes
GO:0032588 trans-Golgi network membrane	IBA GO_REF:0000033	KEEP AS NON CORE	Summary: trans-Golgi network membrane is plausible as a context-specific PICK1 localization, binding, or downstream process, but it is secondary to the core PDZ/BAR receptor-trafficking function. Reason: trans-Golgi network membrane is secondary to PICK1 membrane protein trafficking and synaptic receptor organization. Supporting Evidence: file:human/PICK1/PICK1-deep-research-falcon.md Across the recent literature, PICK1’s primary molecular role is best described as a PDZ/BAR scaffold that regulates the trafficking and surface availability of membrane proteins—especially AMPA-type glutamate receptors—by coordinating protein complex assembly with membrane remodeling and endocytic/recycling processes file:human/PICK1/PICK1-deep-research-falcon.md Human PICK1 (Q9NRD5) is best annotated as a PDZ/BAR scaffolding and membrane-remodeling protein that controls membrane protein trafficking, with the strongest 2023–2024 evidence supporting roles in AMPAR (GluA2/3) internalization/recycling and synaptic plasticity through phosphorylation-dependent partner switching and regulated complex formation.
GO:0097062 dendritic spine maintenance	IBA GO_REF:0000033	ACCEPT	Summary: Dendritic spine maintenance is supported by PICK1 roles in AMPAR trafficking and synaptic plasticity. Reason: dendritic spine maintenance is supported as part of PICK1 PDZ/BAR scaffold, membrane-remodeling, or synaptic receptor-trafficking function. Supporting Evidence: file:human/PICK1/PICK1-deep-research-falcon.md Across the recent literature, PICK1’s primary molecular role is best described as a PDZ/BAR scaffold that regulates the trafficking and surface availability of membrane proteins—especially AMPA-type glutamate receptors—by coordinating protein complex assembly with membrane remodeling and endocytic/recycling processes file:human/PICK1/PICK1-deep-research-falcon.md PICK1 is described as enriched in brain and localized to pre- and postsynaptic compartments, consistent with its role in regulating synaptic receptor trafficking
GO:0002092 positive regulation of receptor internalization	IBA GO_REF:0000033	ACCEPT	Summary: Positive regulation of receptor internalization is a core PICK1-supported process for AMPAR GluA2 trafficking. Reason: positive regulation of receptor internalization is supported as part of PICK1 PDZ/BAR scaffold, membrane-remodeling, or synaptic receptor-trafficking function. Supporting Evidence: file:human/PICK1/PICK1-deep-research-falcon.md In vivo evidence from mouse hippocampus (kainic acid model) supports a mechanistic switch in which GluA2 Ser880 phosphorylation promotes dissociation from GRIP1 and association with PICK1, driving AMPAR endocytosis/internalization; PP2A-mediated dephosphorylation reverses this and disfavors PICK1 association file:human/PICK1/PICK1-deep-research-falcon.md Across the recent literature, PICK1’s primary molecular role is best described as a PDZ/BAR scaffold that regulates the trafficking and surface availability of membrane proteins—especially AMPA-type glutamate receptors—by coordinating protein complex assembly with membrane remodeling and endocytic/recycling processes
GO:0005080 protein kinase C binding	IBA GO_REF:0000033	ACCEPT	Summary: Protein kinase C binding is supported by PICK1 identity as a PKC-alpha-binding protein. Reason: protein kinase C binding is supported as part of PICK1 PDZ/BAR scaffold, membrane-remodeling, or synaptic receptor-trafficking function. Supporting Evidence: file:human/PICK1/PICK1-deep-research-falcon.md PICK1 was originally cloned/recognized as a PKCα-binding protein, a point reiterated in 2023 work on synaptic receptor regulation
GO:0034315 regulation of Arp2/3 complex-mediated actin nucleation	IBA GO_REF:0000033	KEEP AS NON CORE	Summary: regulation of Arp2/3 complex-mediated actin nucleation is plausible as a context-specific PICK1 localization, binding, or downstream process, but it is secondary to the core PDZ/BAR receptor-trafficking function. Reason: regulation of Arp2/3 complex-mediated actin nucleation is secondary to PICK1 membrane protein trafficking and synaptic receptor organization. Supporting Evidence: file:human/PICK1/PICK1-deep-research-falcon.md Across the recent literature, PICK1’s primary molecular role is best described as a PDZ/BAR scaffold that regulates the trafficking and surface availability of membrane proteins—especially AMPA-type glutamate receptors—by coordinating protein complex assembly with membrane remodeling and endocytic/recycling processes file:human/PICK1/PICK1-deep-research-falcon.md Human PICK1 (Q9NRD5) is best annotated as a PDZ/BAR scaffolding and membrane-remodeling protein that controls membrane protein trafficking, with the strongest 2023–2024 evidence supporting roles in AMPAR (GluA2/3) internalization/recycling and synaptic plasticity through phosphorylation-dependent partner switching and regulated complex formation.
GO:0003779 actin binding	IEA GO_REF:0000043	KEEP AS NON CORE	Summary: actin binding is plausible as a context-specific PICK1 localization, binding, or downstream process, but it is secondary to the core PDZ/BAR receptor-trafficking function. Reason: actin binding is secondary to PICK1 membrane protein trafficking and synaptic receptor organization. Supporting Evidence: file:human/PICK1/PICK1-deep-research-falcon.md Across the recent literature, PICK1’s primary molecular role is best described as a PDZ/BAR scaffold that regulates the trafficking and surface availability of membrane proteins—especially AMPA-type glutamate receptors—by coordinating protein complex assembly with membrane remodeling and endocytic/recycling processes file:human/PICK1/PICK1-deep-research-falcon.md Human PICK1 (Q9NRD5) is best annotated as a PDZ/BAR scaffolding and membrane-remodeling protein that controls membrane protein trafficking, with the strongest 2023–2024 evidence supporting roles in AMPAR (GluA2/3) internalization/recycling and synaptic plasticity through phosphorylation-dependent partner switching and regulated complex formation.
GO:0005737 cytoplasm	IEA GO_REF:0000117	KEEP AS NON CORE	Summary: cytoplasm is plausible as a context-specific PICK1 localization, binding, or downstream process, but it is secondary to the core PDZ/BAR receptor-trafficking function. Reason: cytoplasm is secondary to PICK1 membrane protein trafficking and synaptic receptor organization. Supporting Evidence: file:human/PICK1/PICK1-deep-research-falcon.md A 2024 Molecular Biology of the Cell study reports that in nonpolarized cells PICK1 is typically cytosolic, but under sodium arsenite stress it relocalizes to perinuclear aggresomes, identifying PICK1 as a stress-responsive organizer of protein sequestration/aggregation compartments
GO:0005856 cytoskeleton	IEA GO_REF:0000044	KEEP AS NON CORE	Summary: cytoskeleton is plausible as a context-specific PICK1 localization, binding, or downstream process, but it is secondary to the core PDZ/BAR receptor-trafficking function. Reason: cytoskeleton is secondary to PICK1 membrane protein trafficking and synaptic receptor organization. Supporting Evidence: file:human/PICK1/PICK1-deep-research-falcon.md Across the recent literature, PICK1’s primary molecular role is best described as a PDZ/BAR scaffold that regulates the trafficking and surface availability of membrane proteins—especially AMPA-type glutamate receptors—by coordinating protein complex assembly with membrane remodeling and endocytic/recycling processes file:human/PICK1/PICK1-deep-research-falcon.md Human PICK1 (Q9NRD5) is best annotated as a PDZ/BAR scaffolding and membrane-remodeling protein that controls membrane protein trafficking, with the strongest 2023–2024 evidence supporting roles in AMPAR (GluA2/3) internalization/recycling and synaptic plasticity through phosphorylation-dependent partner switching and regulated complex formation.
GO:0014069 postsynaptic density	IEA GO_REF:0000044	ACCEPT	Summary: Postsynaptic density localization is supported by PICK1 action at postsynaptic AMPAR complexes. Reason: postsynaptic density is supported as part of PICK1 PDZ/BAR scaffold, membrane-remodeling, or synaptic receptor-trafficking function. Supporting Evidence: file:human/PICK1/PICK1-deep-research-falcon.md PICK1 is described as enriched in brain and localized to pre- and postsynaptic compartments, consistent with its role in regulating synaptic receptor trafficking file:human/PICK1/PICK1-deep-research-falcon.md Across the recent literature, PICK1’s primary molecular role is best described as a PDZ/BAR scaffold that regulates the trafficking and surface availability of membrane proteins—especially AMPA-type glutamate receptors—by coordinating protein complex assembly with membrane remodeling and endocytic/recycling processes
GO:0016020 membrane	IEA GO_REF:0000044	KEEP AS NON CORE	Summary: membrane is plausible as a context-specific PICK1 localization, binding, or downstream process, but it is secondary to the core PDZ/BAR receptor-trafficking function. Reason: membrane is secondary to PICK1 membrane protein trafficking and synaptic receptor organization. Supporting Evidence: file:human/PICK1/PICK1-deep-research-falcon.md Across the recent literature, PICK1’s primary molecular role is best described as a PDZ/BAR scaffold that regulates the trafficking and surface availability of membrane proteins—especially AMPA-type glutamate receptors—by coordinating protein complex assembly with membrane remodeling and endocytic/recycling processes file:human/PICK1/PICK1-deep-research-falcon.md Human PICK1 (Q9NRD5) is best annotated as a PDZ/BAR scaffolding and membrane-remodeling protein that controls membrane protein trafficking, with the strongest 2023–2024 evidence supporting roles in AMPAR (GluA2/3) internalization/recycling and synaptic plasticity through phosphorylation-dependent partner switching and regulated complex formation.
GO:0019904 protein domain specific binding	IEA GO_REF:0000002	ACCEPT	Summary: Protein domain specific binding is supported by PICK1 PDZ-domain recognition of receptor/cargo C-terminal motifs. Reason: protein domain specific binding is supported as part of PICK1 PDZ/BAR scaffold, membrane-remodeling, or synaptic receptor-trafficking function. Supporting Evidence: file:human/PICK1/PICK1-deep-research-falcon.md PDZ domain (protein interaction module): In AMPAR biology, authoritative review evidence states that the GluA2 C-terminus contains a PDZ ligand that binds directly to PICK1 (and GRIP1), and that PICK1 binds GluA2 via its PDZ domain
GO:0043005 neuron projection	IEA GO_REF:0000043	ACCEPT	Summary: Neuron projection localization is consistent with PICK1 function in pre- and postsynaptic neuronal compartments. Reason: neuron projection is supported as part of PICK1 PDZ/BAR scaffold, membrane-remodeling, or synaptic receptor-trafficking function. Supporting Evidence: file:human/PICK1/PICK1-deep-research-falcon.md PICK1 is described as enriched in brain and localized to pre- and postsynaptic compartments, consistent with its role in regulating synaptic receptor trafficking
GO:0045202 synapse	IEA GO_REF:0000120	ACCEPT	Summary: Synapse localization is supported by PICK1 enrichment in pre- and postsynaptic compartments. Reason: synapse is supported as part of PICK1 PDZ/BAR scaffold, membrane-remodeling, or synaptic receptor-trafficking function. Supporting Evidence: file:human/PICK1/PICK1-deep-research-falcon.md PICK1 is described as enriched in brain and localized to pre- and postsynaptic compartments, consistent with its role in regulating synaptic receptor trafficking
GO:0046872 metal ion binding	IEA GO_REF:0000043	MARK AS OVER ANNOTATED	Summary: Metal ion binding is not the functionally informative annotation for PICK1 compared with PDZ/BAR scaffold and membrane-remodeling activities. Reason: metal ion binding is less informative than the specific PICK1 scaffold mechanism. Supporting Evidence: file:human/PICK1/PICK1-deep-research-falcon.md PICK1 is a dual-domain scaffolding/adaptor protein that couples (i) PDZ-domain–mediated binding to C-terminal motifs on cargo proteins with (ii) BAR/N‑BAR–mediated lipid/membrane binding and remodeling, enabling regulation of membrane protein trafficking and compartmentalization
GO:0048471 perinuclear region of cytoplasm	IEA GO_REF:0000044	KEEP AS NON CORE	Summary: perinuclear region of cytoplasm is plausible as a context-specific PICK1 localization, binding, or downstream process, but it is secondary to the core PDZ/BAR receptor-trafficking function. Reason: perinuclear region of cytoplasm is secondary to PICK1 membrane protein trafficking and synaptic receptor organization. Supporting Evidence: file:human/PICK1/PICK1-deep-research-falcon.md A 2024 Molecular Biology of the Cell study reports that in nonpolarized cells PICK1 is typically cytosolic, but under sodium arsenite stress it relocalizes to perinuclear aggresomes, identifying PICK1 as a stress-responsive organizer of protein sequestration/aggregation compartments
GO:0005515 protein binding	IPI PMID:11343649 Functional interaction between monoamine plasma membrane tra...	MARK AS OVER ANNOTATED	Summary: Protein binding is too generic for PICK1; PDZ-domain binding, PKC binding, receptor binding, and identical protein binding are more informative. Reason: protein binding is less informative than the specific PICK1 scaffold mechanism. Supporting Evidence: file:human/PICK1/PICK1-deep-research-falcon.md PICK1 is a dual-domain scaffolding/adaptor protein that couples (i) PDZ-domain–mediated binding to C-terminal motifs on cargo proteins with (ii) BAR/N‑BAR–mediated lipid/membrane binding and remodeling, enabling regulation of membrane protein trafficking and compartmentalization file:human/PICK1/PICK1-deep-research-falcon.md PDZ domain (protein interaction module): In AMPAR biology, authoritative review evidence states that the GluA2 C-terminus contains a PDZ ligand that binds directly to PICK1 (and GRIP1), and that PICK1 binds GluA2 via its PDZ domain
GO:0005515 protein binding	IPI PMID:11802773 Interaction of the synaptic protein PICK1 (protein interacti...	MARK AS OVER ANNOTATED	Summary: Protein binding is too generic for PICK1; PDZ-domain binding, PKC binding, receptor binding, and identical protein binding are more informative. Reason: protein binding is less informative than the specific PICK1 scaffold mechanism. Supporting Evidence: file:human/PICK1/PICK1-deep-research-falcon.md PICK1 is a dual-domain scaffolding/adaptor protein that couples (i) PDZ-domain–mediated binding to C-terminal motifs on cargo proteins with (ii) BAR/N‑BAR–mediated lipid/membrane binding and remodeling, enabling regulation of membrane protein trafficking and compartmentalization file:human/PICK1/PICK1-deep-research-falcon.md PDZ domain (protein interaction module): In AMPAR biology, authoritative review evidence states that the GluA2 C-terminus contains a PDZ ligand that binds directly to PICK1 (and GRIP1), and that PICK1 binds GluA2 via its PDZ domain
GO:0005515 protein binding	IPI PMID:16713569 A protein-protein interaction network for human inherited at...	MARK AS OVER ANNOTATED	Summary: Protein binding is too generic for PICK1; PDZ-domain binding, PKC binding, receptor binding, and identical protein binding are more informative. Reason: protein binding is less informative than the specific PICK1 scaffold mechanism. Supporting Evidence: file:human/PICK1/PICK1-deep-research-falcon.md PICK1 is a dual-domain scaffolding/adaptor protein that couples (i) PDZ-domain–mediated binding to C-terminal motifs on cargo proteins with (ii) BAR/N‑BAR–mediated lipid/membrane binding and remodeling, enabling regulation of membrane protein trafficking and compartmentalization file:human/PICK1/PICK1-deep-research-falcon.md PDZ domain (protein interaction module): In AMPAR biology, authoritative review evidence states that the GluA2 C-terminus contains a PDZ ligand that binds directly to PICK1 (and GRIP1), and that PICK1 binds GluA2 via its PDZ domain
GO:0005515 protein binding	IPI PMID:21653829 Protein interactome reveals converging molecular pathways am...	MARK AS OVER ANNOTATED	Summary: Protein binding is too generic for PICK1; PDZ-domain binding, PKC binding, receptor binding, and identical protein binding are more informative. Reason: protein binding is less informative than the specific PICK1 scaffold mechanism. Supporting Evidence: file:human/PICK1/PICK1-deep-research-falcon.md PICK1 is a dual-domain scaffolding/adaptor protein that couples (i) PDZ-domain–mediated binding to C-terminal motifs on cargo proteins with (ii) BAR/N‑BAR–mediated lipid/membrane binding and remodeling, enabling regulation of membrane protein trafficking and compartmentalization file:human/PICK1/PICK1-deep-research-falcon.md PDZ domain (protein interaction module): In AMPAR biology, authoritative review evidence states that the GluA2 C-terminus contains a PDZ ligand that binds directly to PICK1 (and GRIP1), and that PICK1 binds GluA2 via its PDZ domain
GO:0005515 protein binding	IPI PMID:26787460 Proteomic peptide phage display uncovers novel interactions ...	MARK AS OVER ANNOTATED	Summary: Protein binding is too generic for PICK1; PDZ-domain binding, PKC binding, receptor binding, and identical protein binding are more informative. Reason: protein binding is less informative than the specific PICK1 scaffold mechanism. Supporting Evidence: file:human/PICK1/PICK1-deep-research-falcon.md PICK1 is a dual-domain scaffolding/adaptor protein that couples (i) PDZ-domain–mediated binding to C-terminal motifs on cargo proteins with (ii) BAR/N‑BAR–mediated lipid/membrane binding and remodeling, enabling regulation of membrane protein trafficking and compartmentalization file:human/PICK1/PICK1-deep-research-falcon.md PDZ domain (protein interaction module): In AMPAR biology, authoritative review evidence states that the GluA2 C-terminus contains a PDZ ligand that binds directly to PICK1 (and GRIP1), and that PICK1 binds GluA2 via its PDZ domain
GO:0005515 protein binding	IPI PMID:28514442 Architecture of the human interactome defines protein commun...	MARK AS OVER ANNOTATED	Summary: Protein binding is too generic for PICK1; PDZ-domain binding, PKC binding, receptor binding, and identical protein binding are more informative. Reason: protein binding is less informative than the specific PICK1 scaffold mechanism. Supporting Evidence: file:human/PICK1/PICK1-deep-research-falcon.md PICK1 is a dual-domain scaffolding/adaptor protein that couples (i) PDZ-domain–mediated binding to C-terminal motifs on cargo proteins with (ii) BAR/N‑BAR–mediated lipid/membrane binding and remodeling, enabling regulation of membrane protein trafficking and compartmentalization file:human/PICK1/PICK1-deep-research-falcon.md PDZ domain (protein interaction module): In AMPAR biology, authoritative review evidence states that the GluA2 C-terminus contains a PDZ ligand that binds directly to PICK1 (and GRIP1), and that PICK1 binds GluA2 via its PDZ domain
GO:0005515 protein binding	IPI PMID:31413325 HENA, heterogeneous network-based data set for Alzheimer's d...	MARK AS OVER ANNOTATED	Summary: Protein binding is too generic for PICK1; PDZ-domain binding, PKC binding, receptor binding, and identical protein binding are more informative. Reason: protein binding is less informative than the specific PICK1 scaffold mechanism. Supporting Evidence: file:human/PICK1/PICK1-deep-research-falcon.md PICK1 is a dual-domain scaffolding/adaptor protein that couples (i) PDZ-domain–mediated binding to C-terminal motifs on cargo proteins with (ii) BAR/N‑BAR–mediated lipid/membrane binding and remodeling, enabling regulation of membrane protein trafficking and compartmentalization file:human/PICK1/PICK1-deep-research-falcon.md PDZ domain (protein interaction module): In AMPAR biology, authoritative review evidence states that the GluA2 C-terminus contains a PDZ ligand that binds directly to PICK1 (and GRIP1), and that PICK1 binds GluA2 via its PDZ domain
GO:0005515 protein binding	IPI PMID:32296183 A reference map of the human binary protein interactome.	MARK AS OVER ANNOTATED	Summary: Protein binding is too generic for PICK1; PDZ-domain binding, PKC binding, receptor binding, and identical protein binding are more informative. Reason: protein binding is less informative than the specific PICK1 scaffold mechanism. Supporting Evidence: file:human/PICK1/PICK1-deep-research-falcon.md PICK1 is a dual-domain scaffolding/adaptor protein that couples (i) PDZ-domain–mediated binding to C-terminal motifs on cargo proteins with (ii) BAR/N‑BAR–mediated lipid/membrane binding and remodeling, enabling regulation of membrane protein trafficking and compartmentalization file:human/PICK1/PICK1-deep-research-falcon.md PDZ domain (protein interaction module): In AMPAR biology, authoritative review evidence states that the GluA2 C-terminus contains a PDZ ligand that binds directly to PICK1 (and GRIP1), and that PICK1 binds GluA2 via its PDZ domain
GO:0005515 protein binding	IPI PMID:32814053 Interactome Mapping Provides a Network of Neurodegenerative ...	MARK AS OVER ANNOTATED	Summary: Protein binding is too generic for PICK1; PDZ-domain binding, PKC binding, receptor binding, and identical protein binding are more informative. Reason: protein binding is less informative than the specific PICK1 scaffold mechanism. Supporting Evidence: file:human/PICK1/PICK1-deep-research-falcon.md PICK1 is a dual-domain scaffolding/adaptor protein that couples (i) PDZ-domain–mediated binding to C-terminal motifs on cargo proteins with (ii) BAR/N‑BAR–mediated lipid/membrane binding and remodeling, enabling regulation of membrane protein trafficking and compartmentalization file:human/PICK1/PICK1-deep-research-falcon.md PDZ domain (protein interaction module): In AMPAR biology, authoritative review evidence states that the GluA2 C-terminus contains a PDZ ligand that binds directly to PICK1 (and GRIP1), and that PICK1 binds GluA2 via its PDZ domain
GO:0005515 protein binding	IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling...	MARK AS OVER ANNOTATED	Summary: Protein binding is too generic for PICK1; PDZ-domain binding, PKC binding, receptor binding, and identical protein binding are more informative. Reason: protein binding is less informative than the specific PICK1 scaffold mechanism. Supporting Evidence: file:human/PICK1/PICK1-deep-research-falcon.md PICK1 is a dual-domain scaffolding/adaptor protein that couples (i) PDZ-domain–mediated binding to C-terminal motifs on cargo proteins with (ii) BAR/N‑BAR–mediated lipid/membrane binding and remodeling, enabling regulation of membrane protein trafficking and compartmentalization file:human/PICK1/PICK1-deep-research-falcon.md PDZ domain (protein interaction module): In AMPAR biology, authoritative review evidence states that the GluA2 C-terminus contains a PDZ ligand that binds directly to PICK1 (and GRIP1), and that PICK1 binds GluA2 via its PDZ domain
GO:0005515 protein binding	IPI PMID:36115835 Quantitative fragmentomics allow affinity mapping of interac...	MARK AS OVER ANNOTATED	Summary: Protein binding is too generic for PICK1; PDZ-domain binding, PKC binding, receptor binding, and identical protein binding are more informative. Reason: protein binding is less informative than the specific PICK1 scaffold mechanism. Supporting Evidence: file:human/PICK1/PICK1-deep-research-falcon.md PICK1 is a dual-domain scaffolding/adaptor protein that couples (i) PDZ-domain–mediated binding to C-terminal motifs on cargo proteins with (ii) BAR/N‑BAR–mediated lipid/membrane binding and remodeling, enabling regulation of membrane protein trafficking and compartmentalization file:human/PICK1/PICK1-deep-research-falcon.md PDZ domain (protein interaction module): In AMPAR biology, authoritative review evidence states that the GluA2 C-terminus contains a PDZ ligand that binds directly to PICK1 (and GRIP1), and that PICK1 binds GluA2 via its PDZ domain
GO:0005515 protein binding	IPI PMID:37207277 Using brain cell-type-specific protein interactomes to inter...	MARK AS OVER ANNOTATED	Summary: Protein binding is too generic for PICK1; PDZ-domain binding, PKC binding, receptor binding, and identical protein binding are more informative. Reason: protein binding is less informative than the specific PICK1 scaffold mechanism. Supporting Evidence: file:human/PICK1/PICK1-deep-research-falcon.md PICK1 is a dual-domain scaffolding/adaptor protein that couples (i) PDZ-domain–mediated binding to C-terminal motifs on cargo proteins with (ii) BAR/N‑BAR–mediated lipid/membrane binding and remodeling, enabling regulation of membrane protein trafficking and compartmentalization file:human/PICK1/PICK1-deep-research-falcon.md PDZ domain (protein interaction module): In AMPAR biology, authoritative review evidence states that the GluA2 C-terminus contains a PDZ ligand that binds directly to PICK1 (and GRIP1), and that PICK1 binds GluA2 via its PDZ domain
GO:0042802 identical protein binding	IPI PMID:32296183 A reference map of the human binary protein interactome.	ACCEPT	Summary: Identical protein binding is supported by BAR-domain homodimerization and higher-order PICK1 assembly. Reason: identical protein binding is supported as part of PICK1 PDZ/BAR scaffold, membrane-remodeling, or synaptic receptor-trafficking function. Supporting Evidence: file:human/PICK1/PICK1-deep-research-falcon.md BAR / N‑BAR domain (membrane remodeling module): BAR domains are classically crescent-shaped, lipid-binding modules involved in membrane curvature during trafficking.
GO:0005829 cytosol	IDA GO_REF:0000052	KEEP AS NON CORE	Summary: cytosol is plausible as a context-specific PICK1 localization, binding, or downstream process, but it is secondary to the core PDZ/BAR receptor-trafficking function. Reason: cytosol is secondary to PICK1 membrane protein trafficking and synaptic receptor organization. Supporting Evidence: file:human/PICK1/PICK1-deep-research-falcon.md A 2024 Molecular Biology of the Cell study reports that in nonpolarized cells PICK1 is typically cytosolic, but under sodium arsenite stress it relocalizes to perinuclear aggresomes, identifying PICK1 as a stress-responsive organizer of protein sequestration/aggregation compartments
GO:0005515 protein binding	IPI PMID:16314870 Serine racemase binds to PICK1: potential relevance to schiz...	MARK AS OVER ANNOTATED	Summary: Protein binding is too generic for PICK1; PDZ-domain binding, PKC binding, receptor binding, and identical protein binding are more informative. Reason: protein binding is less informative than the specific PICK1 scaffold mechanism. Supporting Evidence: file:human/PICK1/PICK1-deep-research-falcon.md PICK1 is a dual-domain scaffolding/adaptor protein that couples (i) PDZ-domain–mediated binding to C-terminal motifs on cargo proteins with (ii) BAR/N‑BAR–mediated lipid/membrane binding and remodeling, enabling regulation of membrane protein trafficking and compartmentalization file:human/PICK1/PICK1-deep-research-falcon.md PDZ domain (protein interaction module): In AMPAR biology, authoritative review evidence states that the GluA2 C-terminus contains a PDZ ligand that binds directly to PICK1 (and GRIP1), and that PICK1 binds GluA2 via its PDZ domain
GO:0050796 regulation of insulin secretion	IMP PMID:29768204 An Amphipathic Helix Directs Cellular Membrane Curvature Sen...	KEEP AS NON CORE	Summary: regulation of insulin secretion is plausible as a context-specific PICK1 localization, binding, or downstream process, but it is secondary to the core PDZ/BAR receptor-trafficking function. Reason: regulation of insulin secretion is secondary to PICK1 membrane protein trafficking and synaptic receptor organization. Supporting Evidence: file:human/PICK1/PICK1-deep-research-falcon.md Across the recent literature, PICK1’s primary molecular role is best described as a PDZ/BAR scaffold that regulates the trafficking and surface availability of membrane proteins—especially AMPA-type glutamate receptors—by coordinating protein complex assembly with membrane remodeling and endocytic/recycling processes file:human/PICK1/PICK1-deep-research-falcon.md Human PICK1 (Q9NRD5) is best annotated as a PDZ/BAR scaffolding and membrane-remodeling protein that controls membrane protein trafficking, with the strongest 2023–2024 evidence supporting roles in AMPAR (GluA2/3) internalization/recycling and synaptic plasticity through phosphorylation-dependent partner switching and regulated complex formation.
GO:0140090 membrane curvature sensor activity	IDA PMID:29768204 An Amphipathic Helix Directs Cellular Membrane Curvature Sen...	ACCEPT	Summary: Membrane curvature sensor activity is supported by PICK1 BAR/N-BAR membrane-remodeling function. Reason: membrane curvature sensor activity is supported as part of PICK1 PDZ/BAR scaffold, membrane-remodeling, or synaptic receptor-trafficking function. Supporting Evidence: file:human/PICK1/PICK1-deep-research-falcon.md BAR / N‑BAR domain (membrane remodeling module): BAR domains are classically crescent-shaped, lipid-binding modules involved in membrane curvature during trafficking. file:human/PICK1/PICK1-deep-research-falcon.md PICK1 is a dual-domain scaffolding/adaptor protein that couples (i) PDZ-domain–mediated binding to C-terminal motifs on cargo proteins with (ii) BAR/N‑BAR–mediated lipid/membrane binding and remodeling, enabling regulation of membrane protein trafficking and compartmentalization
GO:0001664 G protein-coupled receptor binding	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: G protein-coupled receptor binding is plausible as a context-specific PICK1 localization, binding, or downstream process, but it is secondary to the core PDZ/BAR receptor-trafficking function. Reason: G protein-coupled receptor binding is secondary to PICK1 membrane protein trafficking and synaptic receptor organization. Supporting Evidence: file:human/PICK1/PICK1-deep-research-falcon.md Across the recent literature, PICK1’s primary molecular role is best described as a PDZ/BAR scaffold that regulates the trafficking and surface availability of membrane proteins—especially AMPA-type glutamate receptors—by coordinating protein complex assembly with membrane remodeling and endocytic/recycling processes file:human/PICK1/PICK1-deep-research-falcon.md Human PICK1 (Q9NRD5) is best annotated as a PDZ/BAR scaffolding and membrane-remodeling protein that controls membrane protein trafficking, with the strongest 2023–2024 evidence supporting roles in AMPAR (GluA2/3) internalization/recycling and synaptic plasticity through phosphorylation-dependent partner switching and regulated complex formation.
GO:0019904 protein domain specific binding	ISS GO_REF:0000024	ACCEPT	Summary: Protein domain specific binding is supported by PICK1 PDZ-domain recognition of receptor/cargo C-terminal motifs. Reason: protein domain specific binding is supported as part of PICK1 PDZ/BAR scaffold, membrane-remodeling, or synaptic receptor-trafficking function. Supporting Evidence: file:human/PICK1/PICK1-deep-research-falcon.md PDZ domain (protein interaction module): In AMPAR biology, authoritative review evidence states that the GluA2 C-terminus contains a PDZ ligand that binds directly to PICK1 (and GRIP1), and that PICK1 binds GluA2 via its PDZ domain
GO:0042802 identical protein binding	ISS GO_REF:0000024	ACCEPT	Summary: Identical protein binding is supported by BAR-domain homodimerization and higher-order PICK1 assembly. Reason: identical protein binding is supported as part of PICK1 PDZ/BAR scaffold, membrane-remodeling, or synaptic receptor-trafficking function. Supporting Evidence: file:human/PICK1/PICK1-deep-research-falcon.md BAR / N‑BAR domain (membrane remodeling module): BAR domains are classically crescent-shaped, lipid-binding modules involved in membrane curvature during trafficking.
GO:0002092 positive regulation of receptor internalization	ISS GO_REF:0000024	ACCEPT	Summary: Positive regulation of receptor internalization is a core PICK1-supported process for AMPAR GluA2 trafficking. Reason: positive regulation of receptor internalization is supported as part of PICK1 PDZ/BAR scaffold, membrane-remodeling, or synaptic receptor-trafficking function. Supporting Evidence: file:human/PICK1/PICK1-deep-research-falcon.md In vivo evidence from mouse hippocampus (kainic acid model) supports a mechanistic switch in which GluA2 Ser880 phosphorylation promotes dissociation from GRIP1 and association with PICK1, driving AMPAR endocytosis/internalization; PP2A-mediated dephosphorylation reverses this and disfavors PICK1 association file:human/PICK1/PICK1-deep-research-falcon.md Across the recent literature, PICK1’s primary molecular role is best described as a PDZ/BAR scaffold that regulates the trafficking and surface availability of membrane proteins—especially AMPA-type glutamate receptors—by coordinating protein complex assembly with membrane remodeling and endocytic/recycling processes
GO:0021782 glial cell development	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: glial cell development is plausible as a context-specific PICK1 localization, binding, or downstream process, but it is secondary to the core PDZ/BAR receptor-trafficking function. Reason: glial cell development is secondary to PICK1 membrane protein trafficking and synaptic receptor organization. Supporting Evidence: file:human/PICK1/PICK1-deep-research-falcon.md Across the recent literature, PICK1’s primary molecular role is best described as a PDZ/BAR scaffold that regulates the trafficking and surface availability of membrane proteins—especially AMPA-type glutamate receptors—by coordinating protein complex assembly with membrane remodeling and endocytic/recycling processes file:human/PICK1/PICK1-deep-research-falcon.md Human PICK1 (Q9NRD5) is best annotated as a PDZ/BAR scaffolding and membrane-remodeling protein that controls membrane protein trafficking, with the strongest 2023–2024 evidence supporting roles in AMPAR (GluA2/3) internalization/recycling and synaptic plasticity through phosphorylation-dependent partner switching and regulated complex formation.
GO:0034316 negative regulation of Arp2/3 complex-mediated actin nucleation	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: negative regulation of Arp2/3 complex-mediated actin nucleation is plausible as a context-specific PICK1 localization, binding, or downstream process, but it is secondary to the core PDZ/BAR receptor-trafficking function. Reason: negative regulation of Arp2/3 complex-mediated actin nucleation is secondary to PICK1 membrane protein trafficking and synaptic receptor organization. Supporting Evidence: file:human/PICK1/PICK1-deep-research-falcon.md Across the recent literature, PICK1’s primary molecular role is best described as a PDZ/BAR scaffold that regulates the trafficking and surface availability of membrane proteins—especially AMPA-type glutamate receptors—by coordinating protein complex assembly with membrane remodeling and endocytic/recycling processes file:human/PICK1/PICK1-deep-research-falcon.md Human PICK1 (Q9NRD5) is best annotated as a PDZ/BAR scaffolding and membrane-remodeling protein that controls membrane protein trafficking, with the strongest 2023–2024 evidence supporting roles in AMPAR (GluA2/3) internalization/recycling and synaptic plasticity through phosphorylation-dependent partner switching and regulated complex formation.
GO:0036294 cellular response to decreased oxygen levels	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: cellular response to decreased oxygen levels is plausible as a context-specific PICK1 localization, binding, or downstream process, but it is secondary to the core PDZ/BAR receptor-trafficking function. Reason: cellular response to decreased oxygen levels is secondary to PICK1 membrane protein trafficking and synaptic receptor organization. Supporting Evidence: file:human/PICK1/PICK1-deep-research-falcon.md Across the recent literature, PICK1’s primary molecular role is best described as a PDZ/BAR scaffold that regulates the trafficking and surface availability of membrane proteins—especially AMPA-type glutamate receptors—by coordinating protein complex assembly with membrane remodeling and endocytic/recycling processes file:human/PICK1/PICK1-deep-research-falcon.md Human PICK1 (Q9NRD5) is best annotated as a PDZ/BAR scaffolding and membrane-remodeling protein that controls membrane protein trafficking, with the strongest 2023–2024 evidence supporting roles in AMPAR (GluA2/3) internalization/recycling and synaptic plasticity through phosphorylation-dependent partner switching and regulated complex formation.
GO:0042149 cellular response to glucose starvation	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: cellular response to glucose starvation is plausible as a context-specific PICK1 localization, binding, or downstream process, but it is secondary to the core PDZ/BAR receptor-trafficking function. Reason: cellular response to glucose starvation is secondary to PICK1 membrane protein trafficking and synaptic receptor organization. Supporting Evidence: file:human/PICK1/PICK1-deep-research-falcon.md Across the recent literature, PICK1’s primary molecular role is best described as a PDZ/BAR scaffold that regulates the trafficking and surface availability of membrane proteins—especially AMPA-type glutamate receptors—by coordinating protein complex assembly with membrane remodeling and endocytic/recycling processes file:human/PICK1/PICK1-deep-research-falcon.md Human PICK1 (Q9NRD5) is best annotated as a PDZ/BAR scaffolding and membrane-remodeling protein that controls membrane protein trafficking, with the strongest 2023–2024 evidence supporting roles in AMPAR (GluA2/3) internalization/recycling and synaptic plasticity through phosphorylation-dependent partner switching and regulated complex formation.
GO:0043005 neuron projection	ISS GO_REF:0000024	ACCEPT	Summary: Neuron projection localization is consistent with PICK1 function in pre- and postsynaptic neuronal compartments. Reason: neuron projection is supported as part of PICK1 PDZ/BAR scaffold, membrane-remodeling, or synaptic receptor-trafficking function. Supporting Evidence: file:human/PICK1/PICK1-deep-research-falcon.md PICK1 is described as enriched in brain and localized to pre- and postsynaptic compartments, consistent with its role in regulating synaptic receptor trafficking
GO:0051015 actin filament binding	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: actin filament binding is plausible as a context-specific PICK1 localization, binding, or downstream process, but it is secondary to the core PDZ/BAR receptor-trafficking function. Reason: actin filament binding is secondary to PICK1 membrane protein trafficking and synaptic receptor organization. Supporting Evidence: file:human/PICK1/PICK1-deep-research-falcon.md Across the recent literature, PICK1’s primary molecular role is best described as a PDZ/BAR scaffold that regulates the trafficking and surface availability of membrane proteins—especially AMPA-type glutamate receptors—by coordinating protein complex assembly with membrane remodeling and endocytic/recycling processes file:human/PICK1/PICK1-deep-research-falcon.md Human PICK1 (Q9NRD5) is best annotated as a PDZ/BAR scaffolding and membrane-remodeling protein that controls membrane protein trafficking, with the strongest 2023–2024 evidence supporting roles in AMPAR (GluA2/3) internalization/recycling and synaptic plasticity through phosphorylation-dependent partner switching and regulated complex formation.
GO:0060292 long-term synaptic depression	ISS GO_REF:0000024	ACCEPT	Summary: Long-term synaptic depression is supported as a synaptic plasticity context for PICK1-mediated AMPAR internalization. Reason: long-term synaptic depression is supported as part of PICK1 PDZ/BAR scaffold, membrane-remodeling, or synaptic receptor-trafficking function. Supporting Evidence: file:human/PICK1/PICK1-deep-research-falcon.md In vivo evidence from mouse hippocampus (kainic acid model) supports a mechanistic switch in which GluA2 Ser880 phosphorylation promotes dissociation from GRIP1 and association with PICK1, driving AMPAR endocytosis/internalization; PP2A-mediated dephosphorylation reverses this and disfavors PICK1 association file:human/PICK1/PICK1-deep-research-falcon.md Human PICK1 (Q9NRD5) is best annotated as a PDZ/BAR scaffolding and membrane-remodeling protein that controls membrane protein trafficking, with the strongest 2023–2024 evidence supporting roles in AMPAR (GluA2/3) internalization/recycling and synaptic plasticity through phosphorylation-dependent partner switching and regulated complex formation.
GO:0071933 Arp2/3 complex binding	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: Arp2/3 complex binding is plausible as a context-specific PICK1 localization, binding, or downstream process, but it is secondary to the core PDZ/BAR receptor-trafficking function. Reason: Arp2/3 complex binding is secondary to PICK1 membrane protein trafficking and synaptic receptor organization. Supporting Evidence: file:human/PICK1/PICK1-deep-research-falcon.md Across the recent literature, PICK1’s primary molecular role is best described as a PDZ/BAR scaffold that regulates the trafficking and surface availability of membrane proteins—especially AMPA-type glutamate receptors—by coordinating protein complex assembly with membrane remodeling and endocytic/recycling processes file:human/PICK1/PICK1-deep-research-falcon.md Human PICK1 (Q9NRD5) is best annotated as a PDZ/BAR scaffolding and membrane-remodeling protein that controls membrane protein trafficking, with the strongest 2023–2024 evidence supporting roles in AMPAR (GluA2/3) internalization/recycling and synaptic plasticity through phosphorylation-dependent partner switching and regulated complex formation.
GO:0097061 dendritic spine organization	ISS GO_REF:0000024	ACCEPT	Summary: Dendritic spine organization is supported through PICK1-dependent AMPAR trafficking and synaptic plasticity. Reason: dendritic spine organization is supported as part of PICK1 PDZ/BAR scaffold, membrane-remodeling, or synaptic receptor-trafficking function. Supporting Evidence: file:human/PICK1/PICK1-deep-research-falcon.md Across the recent literature, PICK1’s primary molecular role is best described as a PDZ/BAR scaffold that regulates the trafficking and surface availability of membrane proteins—especially AMPA-type glutamate receptors—by coordinating protein complex assembly with membrane remodeling and endocytic/recycling processes file:human/PICK1/PICK1-deep-research-falcon.md PICK1 is described as enriched in brain and localized to pre- and postsynaptic compartments, consistent with its role in regulating synaptic receptor trafficking
GO:0097062 dendritic spine maintenance	ISS GO_REF:0000024	ACCEPT	Summary: Dendritic spine maintenance is supported by PICK1 roles in AMPAR trafficking and synaptic plasticity. Reason: dendritic spine maintenance is supported as part of PICK1 PDZ/BAR scaffold, membrane-remodeling, or synaptic receptor-trafficking function. Supporting Evidence: file:human/PICK1/PICK1-deep-research-falcon.md Across the recent literature, PICK1’s primary molecular role is best described as a PDZ/BAR scaffold that regulates the trafficking and surface availability of membrane proteins—especially AMPA-type glutamate receptors—by coordinating protein complex assembly with membrane remodeling and endocytic/recycling processes file:human/PICK1/PICK1-deep-research-falcon.md PICK1 is described as enriched in brain and localized to pre- and postsynaptic compartments, consistent with its role in regulating synaptic receptor trafficking
GO:0005886 plasma membrane	TAS Reactome:R-HSA-416639	ACCEPT	Summary: Plasma membrane localization is supported by PICK1 roles in surface receptor internalization and trafficking. Reason: plasma membrane is supported as part of PICK1 PDZ/BAR scaffold, membrane-remodeling, or synaptic receptor-trafficking function. Supporting Evidence: file:human/PICK1/PICK1-deep-research-falcon.md In vivo evidence from mouse hippocampus (kainic acid model) supports a mechanistic switch in which GluA2 Ser880 phosphorylation promotes dissociation from GRIP1 and association with PICK1, driving AMPAR endocytosis/internalization; PP2A-mediated dephosphorylation reverses this and disfavors PICK1 association file:human/PICK1/PICK1-deep-research-falcon.md Across the recent literature, PICK1’s primary molecular role is best described as a PDZ/BAR scaffold that regulates the trafficking and surface availability of membrane proteins—especially AMPA-type glutamate receptors—by coordinating protein complex assembly with membrane remodeling and endocytic/recycling processes
GO:0005886 plasma membrane	TAS Reactome:R-HSA-416985	ACCEPT	Summary: Plasma membrane localization is supported by PICK1 roles in surface receptor internalization and trafficking. Reason: plasma membrane is supported as part of PICK1 PDZ/BAR scaffold, membrane-remodeling, or synaptic receptor-trafficking function. Supporting Evidence: file:human/PICK1/PICK1-deep-research-falcon.md In vivo evidence from mouse hippocampus (kainic acid model) supports a mechanistic switch in which GluA2 Ser880 phosphorylation promotes dissociation from GRIP1 and association with PICK1, driving AMPAR endocytosis/internalization; PP2A-mediated dephosphorylation reverses this and disfavors PICK1 association file:human/PICK1/PICK1-deep-research-falcon.md Across the recent literature, PICK1’s primary molecular role is best described as a PDZ/BAR scaffold that regulates the trafficking and surface availability of membrane proteins—especially AMPA-type glutamate receptors—by coordinating protein complex assembly with membrane remodeling and endocytic/recycling processes
GO:0005886 plasma membrane	TAS Reactome:R-HSA-421007	ACCEPT	Summary: Plasma membrane localization is supported by PICK1 roles in surface receptor internalization and trafficking. Reason: plasma membrane is supported as part of PICK1 PDZ/BAR scaffold, membrane-remodeling, or synaptic receptor-trafficking function. Supporting Evidence: file:human/PICK1/PICK1-deep-research-falcon.md In vivo evidence from mouse hippocampus (kainic acid model) supports a mechanistic switch in which GluA2 Ser880 phosphorylation promotes dissociation from GRIP1 and association with PICK1, driving AMPAR endocytosis/internalization; PP2A-mediated dephosphorylation reverses this and disfavors PICK1 association file:human/PICK1/PICK1-deep-research-falcon.md Across the recent literature, PICK1’s primary molecular role is best described as a PDZ/BAR scaffold that regulates the trafficking and surface availability of membrane proteins—especially AMPA-type glutamate receptors—by coordinating protein complex assembly with membrane remodeling and endocytic/recycling processes
GO:0030666 endocytic vesicle membrane	TAS Reactome:R-HSA-416639	ACCEPT	Summary: Endocytic vesicle membrane localization is consistent with PICK1-mediated receptor internalization/recycling. Reason: endocytic vesicle membrane is supported as part of PICK1 PDZ/BAR scaffold, membrane-remodeling, or synaptic receptor-trafficking function. Supporting Evidence: file:human/PICK1/PICK1-deep-research-falcon.md In vivo evidence from mouse hippocampus (kainic acid model) supports a mechanistic switch in which GluA2 Ser880 phosphorylation promotes dissociation from GRIP1 and association with PICK1, driving AMPAR endocytosis/internalization; PP2A-mediated dephosphorylation reverses this and disfavors PICK1 association file:human/PICK1/PICK1-deep-research-falcon.md Across the recent literature, PICK1’s primary molecular role is best described as a PDZ/BAR scaffold that regulates the trafficking and surface availability of membrane proteins—especially AMPA-type glutamate receptors—by coordinating protein complex assembly with membrane remodeling and endocytic/recycling processes
GO:0030666 endocytic vesicle membrane	TAS Reactome:R-HSA-421007	ACCEPT	Summary: Endocytic vesicle membrane localization is consistent with PICK1-mediated receptor internalization/recycling. Reason: endocytic vesicle membrane is supported as part of PICK1 PDZ/BAR scaffold, membrane-remodeling, or synaptic receptor-trafficking function. Supporting Evidence: file:human/PICK1/PICK1-deep-research-falcon.md In vivo evidence from mouse hippocampus (kainic acid model) supports a mechanistic switch in which GluA2 Ser880 phosphorylation promotes dissociation from GRIP1 and association with PICK1, driving AMPAR endocytosis/internalization; PP2A-mediated dephosphorylation reverses this and disfavors PICK1 association file:human/PICK1/PICK1-deep-research-falcon.md Across the recent literature, PICK1’s primary molecular role is best described as a PDZ/BAR scaffold that regulates the trafficking and surface availability of membrane proteins—especially AMPA-type glutamate receptors—by coordinating protein complex assembly with membrane remodeling and endocytic/recycling processes
GO:0005737 cytoplasm	IDA PMID:16314870 Serine racemase binds to PICK1: potential relevance to schiz...	KEEP AS NON CORE	Summary: cytoplasm is plausible as a context-specific PICK1 localization, binding, or downstream process, but it is secondary to the core PDZ/BAR receptor-trafficking function. Reason: cytoplasm is secondary to PICK1 membrane protein trafficking and synaptic receptor organization. Supporting Evidence: file:human/PICK1/PICK1-deep-research-falcon.md A 2024 Molecular Biology of the Cell study reports that in nonpolarized cells PICK1 is typically cytosolic, but under sodium arsenite stress it relocalizes to perinuclear aggresomes, identifying PICK1 as a stress-responsive organizer of protein sequestration/aggregation compartments
GO:0005102 signaling receptor binding	ISS GO_REF:0000024	ACCEPT	Summary: Signaling receptor binding is supported by PICK1 PDZ-domain interactions with receptor cargo such as AMPAR subunits. Reason: signaling receptor binding is supported as part of PICK1 PDZ/BAR scaffold, membrane-remodeling, or synaptic receptor-trafficking function. Supporting Evidence: file:human/PICK1/PICK1-deep-research-falcon.md PDZ domain (protein interaction module): In AMPAR biology, authoritative review evidence states that the GluA2 C-terminus contains a PDZ ligand that binds directly to PICK1 (and GRIP1), and that PICK1 binds GluA2 via its PDZ domain file:human/PICK1/PICK1-deep-research-falcon.md Across the recent literature, PICK1’s primary molecular role is best described as a PDZ/BAR scaffold that regulates the trafficking and surface availability of membrane proteins—especially AMPA-type glutamate receptors—by coordinating protein complex assembly with membrane remodeling and endocytic/recycling processes
GO:0043113 receptor clustering	ISS GO_REF:0000024	ACCEPT	Summary: Receptor clustering is supported by PICK1 PDZ/BAR-dependent organization of synaptic receptor complexes. Reason: receptor clustering is supported as part of PICK1 PDZ/BAR scaffold, membrane-remodeling, or synaptic receptor-trafficking function. Supporting Evidence: file:human/PICK1/PICK1-deep-research-falcon.md Across the recent literature, PICK1’s primary molecular role is best described as a PDZ/BAR scaffold that regulates the trafficking and surface availability of membrane proteins—especially AMPA-type glutamate receptors—by coordinating protein complex assembly with membrane remodeling and endocytic/recycling processes file:human/PICK1/PICK1-deep-research-falcon.md PDZ domain (protein interaction module): In AMPAR biology, authoritative review evidence states that the GluA2 C-terminus contains a PDZ ligand that binds directly to PICK1 (and GRIP1), and that PICK1 binds GluA2 via its PDZ domain
GO:0045202 synapse	ISS GO_REF:0000024	ACCEPT	Summary: Synapse localization is supported by PICK1 enrichment in pre- and postsynaptic compartments. Reason: synapse is supported as part of PICK1 PDZ/BAR scaffold, membrane-remodeling, or synaptic receptor-trafficking function. Supporting Evidence: file:human/PICK1/PICK1-deep-research-falcon.md PICK1 is described as enriched in brain and localized to pre- and postsynaptic compartments, consistent with its role in regulating synaptic receptor trafficking
GO:0005080 protein kinase C binding	ISS GO_REF:0000024	ACCEPT	Summary: Protein kinase C binding is supported by PICK1 identity as a PKC-alpha-binding protein. Reason: protein kinase C binding is supported as part of PICK1 PDZ/BAR scaffold, membrane-remodeling, or synaptic receptor-trafficking function. Supporting Evidence: file:human/PICK1/PICK1-deep-research-falcon.md PICK1 was originally cloned/recognized as a PKCα-binding protein, a point reiterated in 2023 work on synaptic receptor regulation
GO:0048471 perinuclear region of cytoplasm	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: perinuclear region of cytoplasm is plausible as a context-specific PICK1 localization, binding, or downstream process, but it is secondary to the core PDZ/BAR receptor-trafficking function. Reason: perinuclear region of cytoplasm is secondary to PICK1 membrane protein trafficking and synaptic receptor organization. Supporting Evidence: file:human/PICK1/PICK1-deep-research-falcon.md A 2024 Molecular Biology of the Cell study reports that in nonpolarized cells PICK1 is typically cytosolic, but under sodium arsenite stress it relocalizes to perinuclear aggresomes, identifying PICK1 as a stress-responsive organizer of protein sequestration/aggregation compartments
GO:0005794 Golgi apparatus	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: Golgi apparatus is plausible as a context-specific PICK1 localization, binding, or downstream process, but it is secondary to the core PDZ/BAR receptor-trafficking function. Reason: Golgi apparatus is secondary to PICK1 membrane protein trafficking and synaptic receptor organization. Supporting Evidence: file:human/PICK1/PICK1-deep-research-falcon.md Across the recent literature, PICK1’s primary molecular role is best described as a PDZ/BAR scaffold that regulates the trafficking and surface availability of membrane proteins—especially AMPA-type glutamate receptors—by coordinating protein complex assembly with membrane remodeling and endocytic/recycling processes file:human/PICK1/PICK1-deep-research-falcon.md Human PICK1 (Q9NRD5) is best annotated as a PDZ/BAR scaffolding and membrane-remodeling protein that controls membrane protein trafficking, with the strongest 2023–2024 evidence supporting roles in AMPAR (GluA2/3) internalization/recycling and synaptic plasticity through phosphorylation-dependent partner switching and regulated complex formation.
GO:0006468 protein phosphorylation	ISS GO_REF:0000024	REMOVE	Summary: PICK1 controls phosphorylation-dependent receptor partner switching as a scaffold, but it does not catalyze protein phosphorylation. Reason: PICK1 is a phosphorylation-dependent scaffold/trafficking regulator, not a kinase. Supporting Evidence: file:human/PICK1/PICK1-deep-research-falcon.md In vivo evidence from mouse hippocampus (kainic acid model) supports a mechanistic switch in which GluA2 Ser880 phosphorylation promotes dissociation from GRIP1 and association with PICK1, driving AMPAR endocytosis/internalization; PP2A-mediated dephosphorylation reverses this and disfavors PICK1 association
GO:0005737 cytoplasm	IDA PMID:11343649 Functional interaction between monoamine plasma membrane tra...	KEEP AS NON CORE	Summary: cytoplasm is plausible as a context-specific PICK1 localization, binding, or downstream process, but it is secondary to the core PDZ/BAR receptor-trafficking function. Reason: cytoplasm is secondary to PICK1 membrane protein trafficking and synaptic receptor organization. Supporting Evidence: file:human/PICK1/PICK1-deep-research-falcon.md A 2024 Molecular Biology of the Cell study reports that in nonpolarized cells PICK1 is typically cytosolic, but under sodium arsenite stress it relocalizes to perinuclear aggresomes, identifying PICK1 as a stress-responsive organizer of protein sequestration/aggregation compartments
GO:0005886 plasma membrane	IDA PMID:11343649 Functional interaction between monoamine plasma membrane tra...	ACCEPT	Summary: Plasma membrane localization is supported by PICK1 roles in surface receptor internalization and trafficking. Reason: plasma membrane is supported as part of PICK1 PDZ/BAR scaffold, membrane-remodeling, or synaptic receptor-trafficking function. Supporting Evidence: file:human/PICK1/PICK1-deep-research-falcon.md In vivo evidence from mouse hippocampus (kainic acid model) supports a mechanistic switch in which GluA2 Ser880 phosphorylation promotes dissociation from GRIP1 and association with PICK1, driving AMPAR endocytosis/internalization; PP2A-mediated dephosphorylation reverses this and disfavors PICK1 association file:human/PICK1/PICK1-deep-research-falcon.md Across the recent literature, PICK1’s primary molecular role is best described as a PDZ/BAR scaffold that regulates the trafficking and surface availability of membrane proteins—especially AMPA-type glutamate receptors—by coordinating protein complex assembly with membrane remodeling and endocytic/recycling processes
GO:0015844 monoamine transport	IDA PMID:11343649 Functional interaction between monoamine plasma membrane tra...	KEEP AS NON CORE	Summary: monoamine transport is plausible as a context-specific PICK1 localization, binding, or downstream process, but it is secondary to the core PDZ/BAR receptor-trafficking function. Reason: monoamine transport is secondary to PICK1 membrane protein trafficking and synaptic receptor organization. Supporting Evidence: file:human/PICK1/PICK1-deep-research-falcon.md Across the recent literature, PICK1’s primary molecular role is best described as a PDZ/BAR scaffold that regulates the trafficking and surface availability of membrane proteins—especially AMPA-type glutamate receptors—by coordinating protein complex assembly with membrane remodeling and endocytic/recycling processes file:human/PICK1/PICK1-deep-research-falcon.md Human PICK1 (Q9NRD5) is best annotated as a PDZ/BAR scaffolding and membrane-remodeling protein that controls membrane protein trafficking, with the strongest 2023–2024 evidence supporting roles in AMPAR (GluA2/3) internalization/recycling and synaptic plasticity through phosphorylation-dependent partner switching and regulated complex formation.
GO:0042734 presynaptic membrane	IDA PMID:11343649 Functional interaction between monoamine plasma membrane tra...	KEEP AS NON CORE	Summary: presynaptic membrane is plausible as a context-specific PICK1 localization, binding, or downstream process, but it is secondary to the core PDZ/BAR receptor-trafficking function. Reason: presynaptic membrane is secondary to PICK1 membrane protein trafficking and synaptic receptor organization. Supporting Evidence: file:human/PICK1/PICK1-deep-research-falcon.md Across the recent literature, PICK1’s primary molecular role is best described as a PDZ/BAR scaffold that regulates the trafficking and surface availability of membrane proteins—especially AMPA-type glutamate receptors—by coordinating protein complex assembly with membrane remodeling and endocytic/recycling processes file:human/PICK1/PICK1-deep-research-falcon.md Human PICK1 (Q9NRD5) is best annotated as a PDZ/BAR scaffolding and membrane-remodeling protein that controls membrane protein trafficking, with the strongest 2023–2024 evidence supporting roles in AMPAR (GluA2/3) internalization/recycling and synaptic plasticity through phosphorylation-dependent partner switching and regulated complex formation.
GO:0045161 neuronal ion channel clustering	TAS PMID:11343649 Functional interaction between monoamine plasma membrane tra...	ACCEPT	Summary: Neuronal ion channel clustering is consistent with PICK1 synaptic receptor clustering and trafficking roles. Reason: neuronal ion channel clustering is supported as part of PICK1 PDZ/BAR scaffold, membrane-remodeling, or synaptic receptor-trafficking function. Supporting Evidence: file:human/PICK1/PICK1-deep-research-falcon.md Across the recent literature, PICK1’s primary molecular role is best described as a PDZ/BAR scaffold that regulates the trafficking and surface availability of membrane proteins—especially AMPA-type glutamate receptors—by coordinating protein complex assembly with membrane remodeling and endocytic/recycling processes file:human/PICK1/PICK1-deep-research-falcon.md PICK1 is described as enriched in brain and localized to pre- and postsynaptic compartments, consistent with its role in regulating synaptic receptor trafficking

Core Functions

PDZ-domain scaffold activity that selects receptor/cargo partners such as AMPAR GluA2/GluA3 and regulates receptor internalization, clustering, and synaptic trafficking.

Molecular Function:

protein domain specific binding

Directly Involved In:

positive regulation of receptor internalization receptor clustering intracellular protein transport long-term synaptic depression

Cellular Locations:

postsynaptic density synapse plasma membrane

Supporting Evidence:

file:human/PICK1/PICK1-deep-research-falcon.md
**PDZ domain (protein interaction module):** In AMPAR biology, authoritative review evidence states that the **GluA2 C-terminus** contains a PDZ ligand that binds directly to **PICK1** (and GRIP1), and that PICK1 binds GluA2 via its PDZ domain
file:human/PICK1/PICK1-deep-research-falcon.md
In vivo evidence from mouse hippocampus (kainic acid model) supports a mechanistic switch in which **GluA2 Ser880 phosphorylation** promotes dissociation from GRIP1 and association with PICK1, driving AMPAR endocytosis/internalization; PP2A-mediated dephosphorylation reverses this and disfavors PICK1 association
file:human/PICK1/PICK1-deep-research-falcon.md
Human **PICK1 (Q9NRD5)** is best annotated as a **PDZ/BAR scaffolding and membrane-remodeling protein** that controls **membrane protein trafficking**, with the strongest 2023–2024 evidence supporting roles in **AMPAR (GluA2/3) internalization/recycling and synaptic plasticity** through phosphorylation-dependent partner switching and regulated complex formation.

BAR/N-BAR membrane binding and curvature-sensing activity that couples PICK1 cargo complexes to membrane remodeling and compartmentalized trafficking.

Molecular Function:

membrane curvature sensor activity

Directly Involved In:

intracellular protein transport positive regulation of receptor internalization

Cellular Locations:

endocytic vesicle membrane

Supporting Evidence:

file:human/PICK1/PICK1-deep-research-falcon.md
**PICK1 is a dual-domain scaffolding/adaptor protein** that couples (i) **PDZ-domain–mediated binding** to C-terminal motifs on cargo proteins with (ii) **BAR/N‑BAR–mediated lipid/membrane binding and remodeling**, enabling regulation of membrane protein trafficking and compartmentalization
file:human/PICK1/PICK1-deep-research-falcon.md
**BAR / N‑BAR domain (membrane remodeling module):** BAR domains are classically crescent-shaped, lipid-binding modules involved in membrane curvature during trafficking.
file:human/PICK1/PICK1-deep-research-falcon.md
Across the recent literature, PICK1’s primary molecular role is best described as a **PDZ/BAR scaffold that regulates the trafficking and surface availability of membrane proteins—especially AMPA-type glutamate receptors—by coordinating protein complex assembly with membrane remodeling and endocytic/recycling processes**

References

GO_REF:0000002

Gene Ontology annotation through association of InterPro records with GO terms

GO_REF:0000024

Manual transfer of experimentally-verified manual GO annotation data to orthologs by curator judgment of sequence similarity

GO_REF:0000033

Annotation inferences using phylogenetic trees

GO_REF:0000043

Gene Ontology annotation based on UniProtKB/Swiss-Prot keyword mapping

GO_REF:0000044

Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location vocabulary mapping, accompanied by conservative changes to GO terms applied by UniProt

GO_REF:0000052

Gene Ontology annotation based on curation of immunofluorescence data

GO_REF:0000117

Electronic Gene Ontology annotations created by ARBA machine learning models

GO_REF:0000120

Combined Automated Annotation using Multiple IEA Methods

PMID:11343649

Functional interaction between monoamine plasma membrane transporters and the synaptic PDZ domain-containing protein PICK1.

PMID:11802773

Interaction of the synaptic protein PICK1 (protein interacting with C kinase 1) with the non-voltage gated sodium channels BNC1 (brain Na+ channel 1) and ASIC (acid-sensing ion channel).

PMID:16314870

Serine racemase binds to PICK1: potential relevance to schizophrenia.

PMID:16713569

A protein-protein interaction network for human inherited ataxias and disorders of Purkinje cell degeneration.

PMID:21653829

Protein interactome reveals converging molecular pathways among autism disorders.

PMID:26787460

Proteomic peptide phage display uncovers novel interactions of the PDZ1-2 supramodule of syntenin.

PMID:28514442

Architecture of the human interactome defines protein communities and disease networks.

PMID:29768204

An Amphipathic Helix Directs Cellular Membrane Curvature Sensing and Function of the BAR Domain Protein PICK1.

PMID:31413325

HENA, heterogeneous network-based data set for Alzheimer's disease.

PMID:32296183

A reference map of the human binary protein interactome.

PMID:32814053

Interactome Mapping Provides a Network of Neurodegenerative Disease Proteins and Uncovers Widespread Protein Aggregation in Affected Brains.

PMID:33961781

Dual proteome-scale networks reveal cell-specific remodeling of the human interactome.

PMID:36115835

Quantitative fragmentomics allow affinity mapping of interactomes.

PMID:37207277

Using brain cell-type-specific protein interactomes to interpret neurodevelopmental genetic signals in schizophrenia.

Reactome:R-HSA-416639

Trafficking of GluR2-containing AMPA receptors to extrasynaptic sites

Reactome:R-HSA-416985

Trafficking of GluR2-containing AMPA receptors to synapse

Reactome:R-HSA-421007

Endocytosis of Ca impermeable AMPA receptors

file:human/PICK1/PICK1-deep-research-falcon.md

Falcon deep research synthesis for PICK1

Deep Research

Falcon

(PICK1-deep-research-falcon.md)

this with annotations you find in gene/protein databases, but these can be outdated or inaccurate. Falcon Edison Scientific Literature 24 citations 2026-05-12T00:25:00.312279

The research report should be a detailed narrative explaining the function, biological processes, and localization of the gene product. Citations should be given for all claims.

You should prioritize authoritative reviews and primary scientific literature when conducting research. You can supplement
this with annotations you find in gene/protein databases, but these can be outdated or inaccurate.

We are specifically interested in the primary function of the gene - for enzymes, what reaction is catalyzed, and what is the substrate specificity? For transporters, what is the substrate? For structural proteins or adapters, what is the broader structural role? For signaling molecules, what is the role in the pathway.

We are interested in where in or outside the cell the gene product carries out its function.

We are also interested in the signaling or biochemical pathways in which the gene functions. We are less interested in broad pleiotropic effects, except where these elucidate the precise role.

Include evidence where possible. We are interested in both experimental evidence as well as inference from structure, evolution, or bioinformatic analysis. Precise studies should be prioritized over high-throughput, where available.

Research Report: Human PICK1 (UniProt Q9NRD5) — Functional Annotation and Recent Research (2023–2024)

0. Target verification (mandatory)

The gene symbol PICK1 in the retrieved literature corresponds to Protein interacting with C kinase 1 / PRKCA-binding protein in Homo sapiens, matching the UniProt entry Q9NRD5. Multiple 2023–2024 sources explicitly describe PICK1 as a PKCα-binding protein containing both a PDZ domain and a BAR (N‑BAR) domain, consistent with the UniProt-provided domain architecture and synonyms (zhu2023them1muscarinic pages 1-4, song2023investigatingthemechanical pages 1-2).

1. Key concepts and definitions (current understanding)

1.1. What PICK1 is

PICK1 is a dual-domain scaffolding/adaptor protein that couples (i) PDZ-domain–mediated binding to C-terminal motifs on cargo proteins with (ii) BAR/N‑BAR–mediated lipid/membrane binding and remodeling, enabling regulation of membrane protein trafficking and compartmentalization (rathod2023ampaglua2subunit pages 1-4, cao2023molecularmechanismsof pages 1-2, song2023investigatingthemechanical pages 1-2).

1.2. Core domains and what they imply functionally

PDZ domain (protein interaction module): In AMPAR biology, authoritative review evidence states that the GluA2 C-terminus contains a PDZ ligand that binds directly to PICK1 (and GRIP1), and that PICK1 binds GluA2 via its PDZ domain (cao2023molecularmechanismsof pages 1-2). A high-quality 2024 translational study similarly states that the PICK1 PDZ domain interacts with GluA2/GluA3 C termini to regulate receptor trafficking (fadahunsi2024targetingpostsynapticglutamate pages 2-4).
BAR / N‑BAR domain (membrane remodeling module): BAR domains are classically crescent-shaped, lipid-binding modules involved in membrane curvature during trafficking. A 2023 molecular-dynamics study positions PICK1’s N‑BAR dimer as a mechanically specialized membrane-remodeling unit, whose inter-monomer interaction networks and flexibility are proposed to facilitate membrane binding and curvature-related function (song2023investigatingthemechanical pages 1-2, song2023investigatingthemechanical pages 6-7).

1.3. Primary molecular function (functional annotation statement)

Across the recent literature, PICK1’s primary molecular role is best described as a PDZ/BAR scaffold that regulates the trafficking and surface availability of membrane proteins—especially AMPA-type glutamate receptors—by coordinating protein complex assembly with membrane remodeling and endocytic/recycling processes (cao2023molecularmechanismsof pages 1-2, rathod2023ampaglua2subunit pages 1-4, zhu2023them1muscarinic pages 1-4).

2. Biological processes, pathways, and binding partners

2.1. AMPA receptor (AMPAR) trafficking and synaptic plasticity (central pathway)

AMPAR trafficking is the dominant experimentally supported pathway for PICK1 in the retrieved 2023–2024 corpus.

(a) PICK1–GluA2/3 binding and ER-to-synapse trafficking logic
A 2023 AMPAR trafficking review states that PICK1 binds the GluA2 C-terminal domain via its PDZ domain and reports that PICK1 can “stimulate the transportation of GluA2 to the ER membrane”, placing PICK1 activity in early AMPAR biogenesis/trafficking steps (cao2023molecularmechanismsof pages 1-2).

(b) Phosphorylation-dependent switching: GRIP1 ↔ PICK1 on GluA2
In vivo evidence from mouse hippocampus (kainic acid model) supports a mechanistic switch in which GluA2 Ser880 phosphorylation promotes dissociation from GRIP1 and association with PICK1, driving AMPAR endocytosis/internalization; PP2A-mediated dephosphorylation reverses this and disfavors PICK1 association (lee2023pdiaugmentskainic pages 9-11).

(c) Quantitative evidence: increasing GluA2:PICK1 binding promotes internalization
Lee et al. (2023) directly tested whether PICK1-mediated internalization is enhanced when upstream redox regulation perturbs PP2A. In mouse hippocampus, PDI knockdown increased GluA2:PICK1 binding to 1.27-fold of control (p < 0.001), and kainic acid (KA) further enhanced binding under PDI knockdown (lee2023pdiaugmentskainic pages 9-11). The authors interpret this as a mechanism facilitating PICK1-mediated AMPAR internalization via increased GluA2 S880 phosphorylation (lee2023pdiaugmentskainic pages 9-11).

(d) Cholinergic regulation: M1 muscarinic receptor → PICK1 → GluA2 endocytosis
Zhu et al. (2023) report that activation of the M1 muscarinic acetylcholine receptor (77-LH-28-1; 5 µL of 5 µM i.c.v.) promoted surface endocytosis of GluA2, reduced its postsynaptic colocalization with PSD-95, and increased GluA2 Ser880 phosphorylation, with the PICK1–GluA2 interaction required for M1-mediated postsynaptic GluA2 regulation (zhu2023them1muscarinic pages 1-4).

2.2. PKCα (PRKCA) linkage

PICK1 was originally cloned/recognized as a PKCα-binding protein, a point reiterated in 2023 work on synaptic receptor regulation (zhu2023them1muscarinic pages 1-4). In a broader mechanistic synthesis of PICK1 biology, PICK1 is described as targeting activated PKC to AMPAR-associated complexes and thereby influencing receptor surface levels (hendrix2025utilizingafdesignfor pages 8-9).

2.3. CaMKII linkage

In an authoritative 2023 review of AMPAR trafficking, Ca2+-dependent CaMKII activation is reported to promote formation of a CaMKII–PICK1 complex (cao2023molecularmechanismsof pages 1-2). This supports a model in which PICK1 participates in activity-dependent receptor trafficking regulated by Ca2+-linked kinases.

3. Subcellular localization (where PICK1 acts)

3.1. Neuronal compartments: pre-/postsynaptic regions

PICK1 is described as enriched in brain and localized to pre- and postsynaptic compartments, consistent with its role in regulating synaptic receptor trafficking (rathod2023ampaglua2subunit pages 1-4, zhu2023them1muscarinic pages 1-4).

3.2. ER membrane trafficking context

The 2023 AMPAR trafficking review explicitly situates PICK1 in early trafficking steps by stating that PICK1 binds GluA2 and can stimulate its transport to the ER membrane, implying a role beyond the plasma membrane/PSD alone (cao2023molecularmechanismsof pages 1-2).

3.3. Cytosol/perinuclear localization and stress-induced aggresome recruitment

A 2024 Molecular Biology of the Cell study reports that in nonpolarized cells PICK1 is typically cytosolic, but under sodium arsenite stress it relocalizes to perinuclear aggresomes, identifying PICK1 as a stress-responsive organizer of protein sequestration/aggregation compartments (lai2024sodiumarseniteinduces pages 1-2, lai2024sodiumarseniteinduces pages 6-8).

Mechanistically, arsenite:
- Abolished a PDZ-mediated interaction (reported as the PICK1–GluR2 interaction being “completely abolished”) and
- Strongly promoted PICK1 BAR-dependent homodimerization (+544.3 ± 19.52%, P < 0.0001) (lai2024sodiumarseniteinduces pages 6-8).

This connects PICK1’s BAR domain to conditional relocalization and higher-order assembly at perinuclear quality-control organelles (lai2024sodiumarseniteinduces pages 6-8).

4. Recent developments and latest research (prioritizing 2023–2024)

Section	Item	System/Context	Function / Key Result	Quantitative detail	Citation
Domain	PDZ domain	Human PICK1 scaffold	Recognizes C-terminal PDZ ligands on partner proteins; mediates protein-protein interactions central to AMPAR/GluA2 trafficking and synaptic targeting; originally identified in a PKCα-binding protein context	No single universal value reported in the cited excerpts	(rathod2023ampaglua2subunit pages 1-4, zhu2023them1muscarinic pages 1-4, cao2023molecularmechanismsof pages 1-2)
Domain	BAR / N-BAR domain	Human PICK1 scaffold	Lipid-binding, membrane-remodeling, curvature-sensing/inducing module; supports synaptic targeting, membrane association, receptor trafficking, and stress-induced higher-order assembly	MD simulations found directional asymmetry: during downward steering all 67 native inter-monomer residue pairs broke and 17 new pairs formed, whereas upward steering retained 35/67 native pairs and formed 23 new pairs	(zhu2023them1muscarinic pages 1-4, song2023investigatingthemechanical pages 6-7)
Partner / pathway	PRKCA / PKCα	Original PICK1 identification; synaptic signaling	PICK1 is described as a PKCα-binding protein and can target activated PKC to AMPAR-associated complexes, linking phosphorylation to receptor trafficking/plasticity	Qualitative mechanism in cited excerpts	(hendrix2025utilizingafdesignfor pages 8-9, zhu2023them1muscarinic pages 1-4)
Partner / pathway	AMPAR GluA2	Postsynaptic receptor trafficking	Best-established PICK1 cargo/partner in the cited literature; PICK1 binds the GluA2 C-terminus via its PDZ domain and promotes internalization / intracellular retention during LTD-related processes	GluA2:PICK1 binding increased to 1.27-fold after PDI knockdown in mouse hippocampus	(rathod2023ampaglua2subunit pages 1-4, zhu2023them1muscarinic pages 1-4, cao2023molecularmechanismsof pages 1-2, lee2023pdiaugmentskainic pages 9-11)
Partner / pathway	GRIP1	AMPAR trafficking switch	GRIP1 opposes PICK1 on GluA2 trafficking: GRIP1 favors surface expression, while GluA2 S880 phosphorylation promotes GRIP1 dissociation and PICK1 association, driving AMPAR endocytosis	Mechanistic switch centered on GluA2 Ser880 dephosphorylation/phosphorylation; no single effect size in excerpt	(lee2023pdiaugmentskainic pages 9-11)
Partner / pathway	PP2A	GluA2 phosphorylation control	PP2A dephosphorylates GluA2 Ser880, weakening PICK1 association and favoring GRIP1 rebinding; inhibition of PP2A facilitates PICK1-mediated AMPAR internalization	In Lee 2023, oxidation-linked PP2A inhibition was proposed to increase PICK1-mediated internalization; GluA2:PICK1 binding rose 1.27-fold	(lee2023pdiaugmentskainic pages 9-11)
Partner / pathway	CaMKII	Activity-dependent AMPAR regulation	Ca2+-dependent CaMKII activation forms a CaMKII-PICK1 complex in AMPAR trafficking models; both CaMKII and PKC impinge on AMPAR phosphosites relevant to PICK1 function	No standalone numeric value in cited excerpt	(cao2023molecularmechanismsof pages 1-2, lee2023pdiaugmentskainic pages 9-11)
Partner / pathway	M1 muscarinic acetylcholine receptor pathway	Cholinergic control of postsynaptic AMPARs	M1 receptor activation regulates postsynaptic GluA2 surface expression through PICK1-dependent mechanisms, coupling cholinergic signaling to AMPAR endocytosis	77-LH-28-1 delivered i.c.v. at 5 µL of 5 µM; Fsc231 used at 5 µL of 50 µM in the study	(zhu2023them1muscarinic pages 1-4)
Localization	Synapse / postsynaptic density	Neurons	PICK1 is enriched in pre/postsynaptic neural compartments and acts at postsynaptic AMPAR complexes to regulate receptor localization and plasticity	Qualitative localization in cited excerpts	(rathod2023ampaglua2subunit pages 1-4, zhu2023them1muscarinic pages 1-4)
Localization	ER / early secretory pathway	AMPAR trafficking pathway	Review evidence states PICK1 binds GluA2 and stimulates trafficking toward the ER membrane / early secretory pathway steps in AMPAR biogenesis and movement	Qualitative localization in cited excerpt	(cao2023molecularmechanismsof pages 1-2)
Localization	Cytosol / perinuclear region	Nonpolarized cells, heterologous cells	PICK1 is generally cytosolic with occasional perinuclear structures under basal conditions	Qualitative basal localization	(rathod2023ampaglua2subunit pages 1-4, lai2024sodiumarseniteinduces pages 1-2)
Localization	Perinuclear aggresome	Stress response in HEK293T cells	Under arsenite stress, PICK1 relocalizes from diffuse cytosol to perinuclear aggresomes in a BAR-domain-dependent manner	Detergent-insoluble PICK1 increased by ~191.2 ± 20.79 (P = 0.008); soluble fraction decreased by 32.77 ± 3.28% (P = 0.006)	(lai2024sodiumarseniteinduces pages 6-8)
Recent study (2023)	Cao 2023 review	Nervous system / AMPAR trafficking review	Summarizes that GluA2 C-terminal PDZ ligands bind PICK1 and GRIP1; PICK1 binds GluA2 via its PDZ domain and participates in ER-to-synapse trafficking logic and CaMKII-linked regulation	Review, no primary effect size	(cao2023molecularmechanismsof pages 1-2)
Recent study (2023)	Zhu 2023	Mouse brain, M1 mAChR activation	M1 receptor activation promoted postsynaptic GluA2 endocytosis, reduced GluA2-PSD95 colocalization, and increased GluA2 Ser880 phosphorylation in a PICK1-dependent pathway	77-LH-28-1: 5 µL of 5 µM i.c.v.; surface biotinylation used 1 mg/mL sulfo-NHS-LC-biotin; Fsc231: 5 µL of 50 µM; n = 3 replicates	(zhu2023them1muscarinic pages 1-4)
Recent study (2023)	Lee 2023	Mouse hippocampus / kainic acid model	PDI knockdown facilitated PICK1-mediated AMPAR internalization by increasing GluA2 Ser880 phosphorylation and strengthening GluA2:PICK1 interaction	GluA2:PICK1 binding increased to 1.27-fold of control (p < 0.001); KA further enhanced binding in PDI-siRNA animals; n = 7	(lee2023pdiaugmentskainic pages 9-11)
Recent study (2023)	Rathod 2023	In silico PDZ inhibitor discovery	Pharmacophore/docking/MD campaign identified candidate competitive and allosteric PICK1 PDZ inhibitors as potential neurological leads	10 libraries; 340,731,400 molecules and 1,603,779,177 conformers screened; docking scores: Hit_I -9.0, Hit_III -8.9, Hit_IV -9.2, control BQA -8.6 kcal/mol; Hit_II ESOL LogS -3.47	(rathod2023ampaglua2subunit pages 22-26)
Recent study (2023)	Song 2023	Molecular dynamics of PICK1 N-BAR dimer	Mechanical simulations support that helix kinks and interaction networks confer flexibility needed for membrane engagement and asymmetric responses to force	Downward steering broke all 67 native residue pairs and formed 17 new ones; upward steering retained 35/67 and formed 23 new ones	(song2023investigatingthemechanical pages 6-7)
Recent study (2024)	Fadahunsi 2024	Human genetics + obese mouse intervention	GWAS linked PICK1 locus to adiposity; pharmacologic PDZ inhibition with mPD5 produced sustained anti-obesity effects in mice, supporting translational targeting of PICK1	Lead SNP rs4821764 P = 4.9 × 10−12; rs17752670 blood eQTL P = 3.3 × 10−106; 56 mg/kg tolerated; 14-day daily s.c. mPD5 caused 9.8% vehicle-corrected weight loss	(fadahunsi2024targetingpostsynapticglutamate pages 1-2, fadahunsi2024targetingpostsynapticglutamate pages 2-4)
Recent study (2024)	Lai 2024	HEK293T arsenite stress / aggresome biology	Arsenite drove PICK1 BAR-dependent homodimerization, abolished PICK1-GluR2 interaction, shifted PICK1 to aggresomes, and promoted insoluble aggregate formation	PICK1 homodimerization +544.3 ± 19.52% (P < 0.0001); competitive coIP favored PICK1-PICK1 +397.7 ± 4.27% vs PICK1-ICA1 +59.8 ± 3.31%; insoluble pellet +191.2 ± 20.79 (P = 0.008)	(lai2024sodiumarseniteinduces pages 6-8)
Recent study (2024)	Ou 2024	Nasopharyngeal carcinoma cells and xenografts	PICK1 acted as a tumor suppressor in NPC by inhibiting migration, invasion, proliferation, tumor growth, metastasis, and Wnt/β-catenin pathway output	Tail-vein metastasis experiments used n = 5 mice/group; in vitro and in vivo differences were reported as significant with p < 0.01 / *p < 0.001, but effect sizes were not numerically tabulated in the excerpt	(ou2024pick1inhibitsthe pages 2-7)

Table: This table consolidates the core functional annotation of human PICK1, including its PDZ and BAR domains, key partners and pathways, subcellular localization, and major 2023–2024 findings. It is designed to support a narrative research report with quick access to mechanisms, applications, and quantitative study results.

4.1. 2024 translational advance: PDZ-domain targeting for obesity treatment (real-world implementation trend)

Fadahunsi et al. (Science Advances, March 2024, https://doi.org/10.1126/sciadv.adg2636) integrated human genetics and mouse pharmacology:
- Human genetics: loci in/near PICK1 reached genome-wide significance for adiposity traits; the paper reports a lead SNP rs4821764 (P = 4.9 × 10−12) and a blood eQTL for PICK1 rs17752670 (P = 3.3 × 10−106) (fadahunsi2024targetingpostsynapticglutamate pages 1-2, fadahunsi2024targetingpostsynapticglutamate pages 2-4).
- In vivo intervention: a lipidated dimeric PICK1 PDZ-targeting peptide inhibitor (mPD5) produced 9.8% vehicle-corrected weight loss over 14 days (once-daily s.c.), with 56 mg/kg identified as a tolerated dose for chronic studies (fadahunsi2024targetingpostsynapticglutamate pages 2-4).

This is among the strongest recent in vivo demonstrations that PICK1 PDZ targeting can drive a durable physiological phenotype with therapeutic framing (fadahunsi2024targetingpostsynapticglutamate pages 2-4).

4.2. 2024 mechanistic advance: arsenite stress, BAR-domain homodimerization, and aggresomes

Lai et al. (Molecular Biology of the Cell, October 2024, https://doi.org/10.1091/mbc.e24-05-0201) provide quantitative evidence that arsenite selectively promotes PICK1–PICK1 assembly and insolubility:
- PICK1 homodimerization increased +544.3 ± 19.52% (P < 0.0001).
- PICK1 shifted toward detergent-insoluble fractions (pellet ~+191.2 ± 20.79, P = 0.008) with decreased soluble fraction (−32.77 ± 3.28%, P = 0.006) (lai2024sodiumarseniteinduces pages 6-8).

This work expands PICK1 biology beyond synapses, tying it to proteostasis-related compartmentalization relevant to neurodegeneration hypotheses (lai2024sodiumarseniteinduces pages 6-8).

4.3. 2023 mechanistic evidence: PP2A–GluA2 S880–PICK1 axis in vivo

Lee et al. (Scientific Reports, August 2023, https://doi.org/10.1038/s41598-023-41014-7) support a model in which upstream redox state (via PDI) can enhance PICK1-mediated AMPAR internalization by promoting GluA2 S880 phosphorylation and increasing PICK1 binding (lee2023pdiaugmentskainic pages 9-11). The directly quantified increase in GluA2:PICK1 binding (1.27-fold, p < 0.001) provides an experimentally anchored statistic linking PICK1 complex formation to trafficking outcomes (lee2023pdiaugmentskainic pages 9-11).

4.4. 2023–2024 receptor-signaling linkage: M1 mAChR → PICK1 → GluA2 trafficking

Zhu et al. (Psychopharmacology, December 2023, https://doi.org/10.1007/s00213-022-06304-4) provide a pathway-level example of how a GPCR (M1 mAChR) can modulate postsynaptic receptor composition through PICK1-dependent GluA2 trafficking (zhu2023them1muscarinic pages 1-4).

4.5. 2023 structural/biophysical developments: BAR-domain mechanics

Song et al. (Current Protein & Peptide Science, December 2023, https://doi.org/10.2174/1389203724666230522093842) used steered molecular dynamics to infer anisotropic mechanical responses of the PICK1 BAR dimer and detailed inter-monomer contact changes under force (e.g., downward steering broke all 67 native residue pairs; upward steering retained 35/67 and formed 23 new pairs) (song2023investigatingthemechanical pages 6-7, song2023investigatingthemechanical pages 1-2). While computational, this supports current mechanistic thinking that BAR-domain flexibility and interaction networks underlie membrane engagement and curvature-related function (song2023investigatingthemechanical pages 1-2).

5. Current applications and real-world implementations

5.1. Therapeutic targeting of PICK1 PDZ interactions

Three convergent application streams appear in 2023–2024 evidence:
1. Anti-obesity intervention: pharmacological PDZ targeting with mPD5 produces sustained weight loss in obese mice (9.8% vehicle-corrected) (fadahunsi2024targetingpostsynapticglutamate pages 2-4).
2. Neurological disease targeting rationale: PDZ-mediated PICK1–GluA2 interactions are widely framed as druggable points for conditions involving synaptic plasticity dysregulation; 2023 inhibitor-design work positions the PDZ domain as a therapeutic target (rathod2023ampaglua2subunit pages 1-4, rathod2023ampaglua2subunit pages 22-26).
3. Neurodegeneration/proteostasis hypothesis: arsenite-triggered aggresome localization and insolubility suggest PICK1 could participate in stress-linked aggregation pathways, relevant to neurodegenerative disease models (lai2024sodiumarseniteinduces pages 6-8).

5.2. Cancer biology and biomarker potential

Ou et al. (Cell Death & Disease, April 2024, https://doi.org/10.1038/s41419-024-06687-6) report that PICK1 suppresses migration/invasion and inhibits tumor growth and lung metastasis in nasopharyngeal carcinoma models; in tail-vein metastasis experiments they report n = 5 mice per group, and mechanistically find that PICK1 inhibits classical Wnt/β-catenin signaling (β-catenin, c-Myc, CyclinD1) (ou2024pick1inhibitsthe pages 2-7). This positions PICK1 as a potential tumor suppressor/prognostic marker in NPC, although generalization beyond this cancer context requires caution (ou2024pick1inhibitsthe pages 2-7).

6. Expert opinions and authoritative synthesis (with analysis)

6.1. Consensus model

Across authoritative 2023–2024 review/primary sources, the consensus is:
- PICK1 is a PDZ/BAR scaffold whose PDZ interactions with receptor C-termini (especially AMPAR GluA2/3) place it at the center of activity-dependent receptor trafficking and plasticity mechanisms (cao2023molecularmechanismsof pages 1-2, fadahunsi2024targetingpostsynapticglutamate pages 2-4, zhu2023them1muscarinic pages 1-4).
- Phosphorylation state controls partner switching (GRIP1 ↔ PICK1) on GluA2, providing a biochemical mechanism for directional trafficking (surface retention versus internalization) (lee2023pdiaugmentskainic pages 9-11).
- BAR-domain–dependent membrane/proteostasis behaviors extend PICK1’s functions beyond synapses, enabling stress-induced relocalization and assembly (lai2024sodiumarseniteinduces pages 6-8, song2023investigatingthemechanical pages 1-2).

6.2. Reconciling apparent “pleiotropy”

The recent evidence supports a unifying interpretation: PICK1’s apparent pleiotropy (synaptic plasticity, obesity, cancer, aggresomes) is consistent with a core mechanistic toolkit—PDZ-based cargo selection + BAR-based membrane/assembly control—deployed in different cellular contexts (fadahunsi2024targetingpostsynapticglutamate pages 2-4, lai2024sodiumarseniteinduces pages 6-8, ou2024pick1inhibitsthe pages 2-7).

7. Relevant statistics and data points (from recent studies)

Obesity genetics: rs4821764 associated with adiposity traits (P = 4.9 × 10−12); rs17752670 as blood eQTL for PICK1 (P = 3.3 × 10−106) (Science Advances, Mar 2024) (fadahunsi2024targetingpostsynapticglutamate pages 2-4).
Anti-obesity pharmacology: mPD5 caused 9.8% vehicle-corrected weight loss in 14 days; 56 mg/kg tolerated (fadahunsi2024targetingpostsynapticglutamate pages 2-4).
Synaptic trafficking biochemistry: GluA2:PICK1 binding increased to 1.27-fold after PDI knockdown (p < 0.001, n = 7) (Scientific Reports, Aug 2023) (lee2023pdiaugmentskainic pages 9-11).
Stress/aggresome biology: arsenite increased PICK1 homodimerization +544.3 ± 19.52% (P < 0.0001) and increased detergent-insoluble pellet signal ~+191.2 ± 20.79 (P = 0.008) (MBoC, Oct 2024) (lai2024sodiumarseniteinduces pages 6-8).
In silico inhibitor discovery scale: virtual screen of 340,731,400 molecules and 1,603,779,177 conformers; docking scores down to −9.2 kcal/mol for reported hits (Journal of Biomolecular Structure and Dynamics, Nov 2023) (rathod2023ampaglua2subunit pages 22-26).

8. Disease associations (database-level context)

OpenTargets reports PICK1 disease-target associations including Alzheimer disease, Parkinson disease, broader neurodegenerative disease, lysosomal storage disease, and male infertility due to globozoospermia (OpenTargets context) (OpenTargets Search: -PICK1). These associations are useful for hypothesis generation but should be interpreted alongside direct mechanistic evidence from primary studies.

9. Summary (functional annotation statement)

Human PICK1 (Q9NRD5) is best annotated as a PDZ/BAR scaffolding and membrane-remodeling protein that controls membrane protein trafficking, with the strongest 2023–2024 evidence supporting roles in AMPAR (GluA2/3) internalization/recycling and synaptic plasticity through phosphorylation-dependent partner switching and regulated complex formation. Recent work extends PICK1 relevance to system-level phenotypes (obesity via PDZ targeting), stress-driven aggresome biology, and context-specific tumor suppressor signaling via Wnt/β-catenin, motivating ongoing therapeutic and mechanistic studies (fadahunsi2024targetingpostsynapticglutamate pages 2-4, lee2023pdiaugmentskainic pages 9-11, lai2024sodiumarseniteinduces pages 6-8, ou2024pick1inhibitsthe pages 2-7).

References

(zhu2023them1muscarinic pages 1-4): Zengyan Zhu, Wenjuan Wang, Chao Gu, Mei Wang, and Yinghui Yan. The m1 muscarinic acetylcholine receptor regulates the surface expression of the ampa receptor subunit glua2 via pick1. Psychopharmacology, 240:239-248, Dec 2023. URL: https://doi.org/10.1007/s00213-022-06304-4, doi:10.1007/s00213-022-06304-4. This article has 3 citations and is from a peer-reviewed journal.
(song2023investigatingthemechanical pages 1-2): Shenghan Song, Tongtong Li, Amy O. Stevens, Taha Raad, and Yi He. Investigating the mechanical properties and flexibility of n-bar domains in pick1 by molecular dynamics simulations. Current Protein & Peptide Science, 24:865-877, Dec 2023. URL: https://doi.org/10.2174/1389203724666230522093842, doi:10.2174/1389203724666230522093842. This article has 5 citations and is from a peer-reviewed journal.
(rathod2023ampaglua2subunit pages 1-4): Shravan B. Rathod, Pravin B. Prajapati, Ranjana Pal, and Mohmedyasin F. Mansuri. Ampa glua2 subunit competitive inhibitors for pick1 pdz domain: pharmacophore-based virtual screening, molecular docking, molecular dynamics simulation, and adme studies. Journal of Biomolecular Structure and Dynamics, 41:336-351, Nov 2023. URL: https://doi.org/10.1080/07391102.2021.2006086, doi:10.1080/07391102.2021.2006086. This article has 7 citations and is from a peer-reviewed journal.
(cao2023molecularmechanismsof pages 1-2): Yi-Yang Cao, Ling-Ling Wu, Xiao-Nan Li, Yu-Lian Yuan, Wan-Wei Zhao, Jing-Xuan Qi, Xu-Yu Zhao, Natalie Ward, and Jiao Wang. Molecular mechanisms of ampa receptor trafficking in the nervous system. International Journal of Molecular Sciences, 25:111, Dec 2023. URL: https://doi.org/10.3390/ijms25010111, doi:10.3390/ijms25010111. This article has 30 citations.
(fadahunsi2024targetingpostsynapticglutamate pages 2-4): Nicole Fadahunsi, Jonas Petersen, Sophia Metz, Alexander Jakobsen, Cecilie Vad Mathiesen, Alberte Silke Buch-Rasmussen, Nigel Kurgan, Jeppe Kjærgaard Larsen, Rita C. Andersen, Thomas Topilko, Charlotte Svendsen, Mia Apuschkin, Grethe Skovbjerg, Jan Hendrik Schmidt, Grace Houser, Sara Elgaard Jager, Anders Bach, Atul S. Deshmukh, Tuomas O. Kilpeläinen, Kristian Strømgaard, Kenneth L. Madsen, and Christoffer Clemmensen. Targeting postsynaptic glutamate receptor scaffolding proteins psd-95 and pick1 for obesity treatment. Science Advances, Mar 2024. URL: https://doi.org/10.1126/sciadv.adg2636, doi:10.1126/sciadv.adg2636. This article has 17 citations and is from a highest quality peer-reviewed journal.
(song2023investigatingthemechanical pages 6-7): Shenghan Song, Tongtong Li, Amy O. Stevens, Taha Raad, and Yi He. Investigating the mechanical properties and flexibility of n-bar domains in pick1 by molecular dynamics simulations. Current Protein & Peptide Science, 24:865-877, Dec 2023. URL: https://doi.org/10.2174/1389203724666230522093842, doi:10.2174/1389203724666230522093842. This article has 5 citations and is from a peer-reviewed journal.
(lee2023pdiaugmentskainic pages 9-11): Duk-shin Lee, Tae-Hyun Kim, Hana Park, and Ji-eun Kim. Pdi augments kainic acid-induced seizure activity and neuronal death by inhibiting pp2a-glua2-pick1-mediated ampa receptor internalization in the mouse hippocampus. Scientific Reports, Aug 2023. URL: https://doi.org/10.1038/s41598-023-41014-7, doi:10.1038/s41598-023-41014-7. This article has 6 citations and is from a peer-reviewed journal.
(hendrix2025utilizingafdesignfor pages 8-9): Emily Hendrix, Xinyu Xia, Amy O. Stevens, and Yi He. Utilizing afdesign for developing a small molecule inhibitor of pick 1-pdz. Current protein & peptide science, Aug 2025. URL: https://doi.org/10.2174/0113892037316932240806102854, doi:10.2174/0113892037316932240806102854. This article has 2 citations and is from a peer-reviewed journal.
(lai2024sodiumarseniteinduces pages 1-2): John Ho Chun Lai, Marianthi Tsogka, and Jun Xia. Sodium arsenite induces aggresome formation by promoting pick1 bar domain homodimer formation. Molecular Biology of the Cell, Oct 2024. URL: https://doi.org/10.1091/mbc.e24-05-0201, doi:10.1091/mbc.e24-05-0201. This article has 0 citations and is from a domain leading peer-reviewed journal.
(lai2024sodiumarseniteinduces pages 6-8): John Ho Chun Lai, Marianthi Tsogka, and Jun Xia. Sodium arsenite induces aggresome formation by promoting pick1 bar domain homodimer formation. Molecular Biology of the Cell, Oct 2024. URL: https://doi.org/10.1091/mbc.e24-05-0201, doi:10.1091/mbc.e24-05-0201. This article has 0 citations and is from a domain leading peer-reviewed journal.
(rathod2023ampaglua2subunit pages 22-26): Shravan B. Rathod, Pravin B. Prajapati, Ranjana Pal, and Mohmedyasin F. Mansuri. Ampa glua2 subunit competitive inhibitors for pick1 pdz domain: pharmacophore-based virtual screening, molecular docking, molecular dynamics simulation, and adme studies. Journal of Biomolecular Structure and Dynamics, 41:336-351, Nov 2023. URL: https://doi.org/10.1080/07391102.2021.2006086, doi:10.1080/07391102.2021.2006086. This article has 7 citations and is from a peer-reviewed journal.
(fadahunsi2024targetingpostsynapticglutamate pages 1-2): Nicole Fadahunsi, Jonas Petersen, Sophia Metz, Alexander Jakobsen, Cecilie Vad Mathiesen, Alberte Silke Buch-Rasmussen, Nigel Kurgan, Jeppe Kjærgaard Larsen, Rita C. Andersen, Thomas Topilko, Charlotte Svendsen, Mia Apuschkin, Grethe Skovbjerg, Jan Hendrik Schmidt, Grace Houser, Sara Elgaard Jager, Anders Bach, Atul S. Deshmukh, Tuomas O. Kilpeläinen, Kristian Strømgaard, Kenneth L. Madsen, and Christoffer Clemmensen. Targeting postsynaptic glutamate receptor scaffolding proteins psd-95 and pick1 for obesity treatment. Science Advances, Mar 2024. URL: https://doi.org/10.1126/sciadv.adg2636, doi:10.1126/sciadv.adg2636. This article has 17 citations and is from a highest quality peer-reviewed journal.
(ou2024pick1inhibitsthe pages 2-7): Xiaomin Ou, Yingzi Zhang, Yiqing Xu, Yi Liu, Wenzhi Tu, Chaosu Hu, and Yong Liu. Pick1 inhibits the malignancy of nasopharyngeal carcinoma and serves as a novel prognostic marker. Cell Death & Disease, Apr 2024. URL: https://doi.org/10.1038/s41419-024-06687-6, doi:10.1038/s41419-024-06687-6. This article has 3 citations and is from a peer-reviewed journal.
(OpenTargets Search: -PICK1): Open Targets Query (-PICK1, 5 results). Buniello, A. et al. (2025). Open Targets Platform: facilitating therapeutic hypotheses building in drug discovery. Nucleic Acids Research.

Citations

cao2023molecularmechanismsof pages 1-2
fadahunsi2024targetingpostsynapticglutamate pages 2-4
lee2023pdiaugmentskainic pages 9-11
hendrix2025utilizingafdesignfor pages 8-9
lai2024sodiumarseniteinduces pages 6-8
song2023investigatingthemechanical pages 6-7
song2023investigatingthemechanical pages 1-2
lai2024sodiumarseniteinduces pages 1-2
fadahunsi2024targetingpostsynapticglutamate pages 1-2
https://doi.org/10.1126/sciadv.adg2636
https://doi.org/10.1091/mbc.e24-05-0201
https://doi.org/10.1038/s41598-023-41014-7
https://doi.org/10.1007/s00213-022-06304-4
https://doi.org/10.2174/1389203724666230522093842
https://doi.org/10.1038/s41419-024-06687-6
https://doi.org/10.1007/s00213-022-06304-4,
https://doi.org/10.2174/1389203724666230522093842,
https://doi.org/10.1080/07391102.2021.2006086,
https://doi.org/10.3390/ijms25010111,
https://doi.org/10.1126/sciadv.adg2636,
https://doi.org/10.1038/s41598-023-41014-7,
https://doi.org/10.2174/0113892037316932240806102854,
https://doi.org/10.1091/mbc.e24-05-0201,
https://doi.org/10.1038/s41419-024-06687-6,

📄 View Raw YAML

id: Q9NRD5
gene_symbol: PICK1
product_type: PROTEIN
status: COMPLETE
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: 'PICK1 encodes Protein interacting with C kinase 1, a PDZ/BAR-domain scaffold that couples
  cargo-protein binding to membrane binding and curvature-dependent trafficking. Its best-supported core
  role is regulation of membrane protein trafficking, especially AMPA receptor GluA2/GluA3 internalization/recycling
  and synaptic receptor organization, through PDZ-mediated partner selection, PKC-associated signaling,
  and BAR-domain membrane remodeling.'
alternative_products:
  - name: '1'
    id: Q9NRD5-1
  - name: '2'
    id: Q9NRD5-2
    sequence_note: VSP_054902, VSP_054903
existing_annotations:
  - term:
      id: GO:0043113
      label: receptor clustering
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: Receptor clustering is supported by PICK1 PDZ/BAR-dependent organization of synaptic
        receptor complexes.
      action: ACCEPT
      reason: receptor clustering is supported as part of PICK1 PDZ/BAR scaffold,
        membrane-remodeling, or synaptic receptor-trafficking function.
      supported_by:
        - reference_id: file:human/PICK1/PICK1-deep-research-falcon.md
          supporting_text: Across the recent literature, PICK1’s primary molecular role is best
            described as a **PDZ/BAR scaffold that regulates the trafficking and surface
            availability of membrane proteins—especially AMPA-type glutamate receptors—by
            coordinating protein complex assembly with membrane remodeling and endocytic/recycling
            processes**
        - reference_id: file:human/PICK1/PICK1-deep-research-falcon.md
          supporting_text: '**PDZ domain (protein interaction module):** In AMPAR biology, authoritative
            review evidence states that the **GluA2 C-terminus** contains a PDZ ligand that binds directly
            to **PICK1** (and GRIP1), and that PICK1 binds GluA2 via its PDZ domain'
  - term:
      id: GO:0006886
      label: intracellular protein transport
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: Intracellular protein transport is central to PICK1 regulation of AMPAR and other
        membrane-protein trafficking.
      action: ACCEPT
      reason: intracellular protein transport is supported as part of PICK1 PDZ/BAR scaffold,
        membrane-remodeling, or synaptic receptor-trafficking function.
      supported_by:
        - reference_id: file:human/PICK1/PICK1-deep-research-falcon.md
          supporting_text: Across the recent literature, PICK1’s primary molecular role is best
            described as a **PDZ/BAR scaffold that regulates the trafficking and surface
            availability of membrane proteins—especially AMPA-type glutamate receptors—by
            coordinating protein complex assembly with membrane remodeling and endocytic/recycling
            processes**
  - term:
      id: GO:0043005
      label: neuron projection
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: Neuron projection localization is consistent with PICK1 function in pre- and
        postsynaptic neuronal compartments.
      action: ACCEPT
      reason: neuron projection is supported as part of PICK1 PDZ/BAR scaffold, membrane-remodeling,
        or synaptic receptor-trafficking function.
      supported_by:
        - reference_id: file:human/PICK1/PICK1-deep-research-falcon.md
          supporting_text: PICK1 is described as enriched in brain and localized to **pre- and
            postsynaptic compartments**, consistent with its role in regulating synaptic receptor
            trafficking
  - term:
      id: GO:0005543
      label: phospholipid binding
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: Phospholipid binding is supported by the BAR/N-BAR membrane-binding module.
      action: ACCEPT
      reason: phospholipid binding is supported as part of PICK1 PDZ/BAR scaffold,
        membrane-remodeling, or synaptic receptor-trafficking function.
      supported_by:
        - reference_id: file:human/PICK1/PICK1-deep-research-falcon.md
          supporting_text: '**BAR / N‑BAR domain (membrane remodeling module):** BAR domains are classically
            crescent-shaped, lipid-binding modules involved in membrane curvature during trafficking.'
        - reference_id: file:human/PICK1/PICK1-deep-research-falcon.md
          supporting_text: '**PICK1 is a dual-domain scaffolding/adaptor protein** that couples (i) **PDZ-domain–mediated
            binding** to C-terminal motifs on cargo proteins with (ii) **BAR/N‑BAR–mediated lipid/membrane
            binding and remodeling**, enabling regulation of membrane protein trafficking and compartmentalization'
  - term:
      id: GO:0008021
      label: synaptic vesicle
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: Synaptic vesicle localization is consistent with synaptic trafficking functions of
        PICK1.
      action: ACCEPT
      reason: synaptic vesicle is supported as part of PICK1 PDZ/BAR scaffold, membrane-remodeling,
        or synaptic receptor-trafficking function.
      supported_by:
        - reference_id: file:human/PICK1/PICK1-deep-research-falcon.md
          supporting_text: PICK1 is described as enriched in brain and localized to **pre- and
            postsynaptic compartments**, consistent with its role in regulating synaptic receptor
            trafficking
  - term:
      id: GO:0014069
      label: postsynaptic density
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: Postsynaptic density localization is supported by PICK1 action at postsynaptic AMPAR
        complexes.
      action: ACCEPT
      reason: postsynaptic density is supported as part of PICK1 PDZ/BAR scaffold,
        membrane-remodeling, or synaptic receptor-trafficking function.
      supported_by:
        - reference_id: file:human/PICK1/PICK1-deep-research-falcon.md
          supporting_text: PICK1 is described as enriched in brain and localized to **pre- and
            postsynaptic compartments**, consistent with its role in regulating synaptic receptor
            trafficking
        - reference_id: file:human/PICK1/PICK1-deep-research-falcon.md
          supporting_text: Across the recent literature, PICK1’s primary molecular role is best
            described as a **PDZ/BAR scaffold that regulates the trafficking and surface
            availability of membrane proteins—especially AMPA-type glutamate receptors—by
            coordinating protein complex assembly with membrane remodeling and endocytic/recycling
            processes**
  - term:
      id: GO:0032588
      label: trans-Golgi network membrane
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: trans-Golgi network membrane is plausible as a context-specific PICK1 localization,
        binding, or downstream process, but it is secondary to the core PDZ/BAR receptor-trafficking
        function.
      action: KEEP_AS_NON_CORE
      reason: trans-Golgi network membrane is secondary to PICK1 membrane protein trafficking and
        synaptic receptor organization.
      supported_by:
        - reference_id: file:human/PICK1/PICK1-deep-research-falcon.md
          supporting_text: Across the recent literature, PICK1’s primary molecular role is best
            described as a **PDZ/BAR scaffold that regulates the trafficking and surface
            availability of membrane proteins—especially AMPA-type glutamate receptors—by
            coordinating protein complex assembly with membrane remodeling and endocytic/recycling
            processes**
        - reference_id: file:human/PICK1/PICK1-deep-research-falcon.md
          supporting_text: Human **PICK1 (Q9NRD5)** is best annotated as a **PDZ/BAR scaffolding and
            membrane-remodeling protein** that controls **membrane protein trafficking**, with the
            strongest 2023–2024 evidence supporting roles in **AMPAR (GluA2/3)
            internalization/recycling and synaptic plasticity** through phosphorylation-dependent
            partner switching and regulated complex formation.
  - term:
      id: GO:0097062
      label: dendritic spine maintenance
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: Dendritic spine maintenance is supported by PICK1 roles in AMPAR trafficking and
        synaptic plasticity.
      action: ACCEPT
      reason: dendritic spine maintenance is supported as part of PICK1 PDZ/BAR scaffold,
        membrane-remodeling, or synaptic receptor-trafficking function.
      supported_by:
        - reference_id: file:human/PICK1/PICK1-deep-research-falcon.md
          supporting_text: Across the recent literature, PICK1’s primary molecular role is best
            described as a **PDZ/BAR scaffold that regulates the trafficking and surface
            availability of membrane proteins—especially AMPA-type glutamate receptors—by
            coordinating protein complex assembly with membrane remodeling and endocytic/recycling
            processes**
        - reference_id: file:human/PICK1/PICK1-deep-research-falcon.md
          supporting_text: PICK1 is described as enriched in brain and localized to **pre- and
            postsynaptic compartments**, consistent with its role in regulating synaptic receptor
            trafficking
  - term:
      id: GO:0002092
      label: positive regulation of receptor internalization
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: Positive regulation of receptor internalization is a core PICK1-supported process for
        AMPAR GluA2 trafficking.
      action: ACCEPT
      reason: positive regulation of receptor internalization is supported as part of PICK1 PDZ/BAR
        scaffold, membrane-remodeling, or synaptic receptor-trafficking function.
      supported_by:
        - reference_id: file:human/PICK1/PICK1-deep-research-falcon.md
          supporting_text: In vivo evidence from mouse hippocampus (kainic acid model) supports a
            mechanistic switch in which **GluA2 Ser880 phosphorylation** promotes dissociation from
            GRIP1 and association with PICK1, driving AMPAR endocytosis/internalization;
            PP2A-mediated dephosphorylation reverses this and disfavors PICK1 association
        - reference_id: file:human/PICK1/PICK1-deep-research-falcon.md
          supporting_text: Across the recent literature, PICK1’s primary molecular role is best
            described as a **PDZ/BAR scaffold that regulates the trafficking and surface
            availability of membrane proteins—especially AMPA-type glutamate receptors—by
            coordinating protein complex assembly with membrane remodeling and endocytic/recycling
            processes**
  - term:
      id: GO:0005080
      label: protein kinase C binding
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: Protein kinase C binding is supported by PICK1 identity as a PKC-alpha-binding
        protein.
      action: ACCEPT
      reason: protein kinase C binding is supported as part of PICK1 PDZ/BAR scaffold,
        membrane-remodeling, or synaptic receptor-trafficking function.
      supported_by:
        - reference_id: file:human/PICK1/PICK1-deep-research-falcon.md
          supporting_text: PICK1 was originally cloned/recognized as a **PKCα-binding protein**, a
            point reiterated in 2023 work on synaptic receptor regulation
  - term:
      id: GO:0034315
      label: regulation of Arp2/3 complex-mediated actin nucleation
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: regulation of Arp2/3 complex-mediated actin nucleation is plausible as a
        context-specific PICK1 localization, binding, or downstream process, but it is secondary to
        the core PDZ/BAR receptor-trafficking function.
      action: KEEP_AS_NON_CORE
      reason: regulation of Arp2/3 complex-mediated actin nucleation is secondary to PICK1 membrane
        protein trafficking and synaptic receptor organization.
      supported_by:
        - reference_id: file:human/PICK1/PICK1-deep-research-falcon.md
          supporting_text: Across the recent literature, PICK1’s primary molecular role is best
            described as a **PDZ/BAR scaffold that regulates the trafficking and surface
            availability of membrane proteins—especially AMPA-type glutamate receptors—by
            coordinating protein complex assembly with membrane remodeling and endocytic/recycling
            processes**
        - reference_id: file:human/PICK1/PICK1-deep-research-falcon.md
          supporting_text: Human **PICK1 (Q9NRD5)** is best annotated as a **PDZ/BAR scaffolding and
            membrane-remodeling protein** that controls **membrane protein trafficking**, with the
            strongest 2023–2024 evidence supporting roles in **AMPAR (GluA2/3)
            internalization/recycling and synaptic plasticity** through phosphorylation-dependent
            partner switching and regulated complex formation.
  - term:
      id: GO:0003779
      label: actin binding
    evidence_type: IEA
    original_reference_id: GO_REF:0000043
    review:
      summary: actin binding is plausible as a context-specific PICK1 localization, binding, or
        downstream process, but it is secondary to the core PDZ/BAR receptor-trafficking function.
      action: KEEP_AS_NON_CORE
      reason: actin binding is secondary to PICK1 membrane protein trafficking and synaptic receptor
        organization.
      supported_by:
        - reference_id: file:human/PICK1/PICK1-deep-research-falcon.md
          supporting_text: Across the recent literature, PICK1’s primary molecular role is best
            described as a **PDZ/BAR scaffold that regulates the trafficking and surface
            availability of membrane proteins—especially AMPA-type glutamate receptors—by
            coordinating protein complex assembly with membrane remodeling and endocytic/recycling
            processes**
        - reference_id: file:human/PICK1/PICK1-deep-research-falcon.md
          supporting_text: Human **PICK1 (Q9NRD5)** is best annotated as a **PDZ/BAR scaffolding and
            membrane-remodeling protein** that controls **membrane protein trafficking**, with the
            strongest 2023–2024 evidence supporting roles in **AMPAR (GluA2/3)
            internalization/recycling and synaptic plasticity** through phosphorylation-dependent
            partner switching and regulated complex formation.
  - term:
      id: GO:0005737
      label: cytoplasm
    evidence_type: IEA
    original_reference_id: GO_REF:0000117
    review:
      summary: cytoplasm is plausible as a context-specific PICK1 localization, binding, or
        downstream process, but it is secondary to the core PDZ/BAR receptor-trafficking function.
      action: KEEP_AS_NON_CORE
      reason: cytoplasm is secondary to PICK1 membrane protein trafficking and synaptic receptor
        organization.
      supported_by:
        - reference_id: file:human/PICK1/PICK1-deep-research-falcon.md
          supporting_text: A 2024 Molecular Biology of the Cell study reports that in nonpolarized
            cells PICK1 is typically **cytosolic**, but under **sodium arsenite** stress it
            relocalizes to **perinuclear aggresomes**, identifying PICK1 as a stress-responsive
            organizer of protein sequestration/aggregation compartments
  - term:
      id: GO:0005856
      label: cytoskeleton
    evidence_type: IEA
    original_reference_id: GO_REF:0000044
    review:
      summary: cytoskeleton is plausible as a context-specific PICK1 localization, binding, or
        downstream process, but it is secondary to the core PDZ/BAR receptor-trafficking function.
      action: KEEP_AS_NON_CORE
      reason: cytoskeleton is secondary to PICK1 membrane protein trafficking and synaptic receptor
        organization.
      supported_by:
        - reference_id: file:human/PICK1/PICK1-deep-research-falcon.md
          supporting_text: Across the recent literature, PICK1’s primary molecular role is best
            described as a **PDZ/BAR scaffold that regulates the trafficking and surface
            availability of membrane proteins—especially AMPA-type glutamate receptors—by
            coordinating protein complex assembly with membrane remodeling and endocytic/recycling
            processes**
        - reference_id: file:human/PICK1/PICK1-deep-research-falcon.md
          supporting_text: Human **PICK1 (Q9NRD5)** is best annotated as a **PDZ/BAR scaffolding and
            membrane-remodeling protein** that controls **membrane protein trafficking**, with the
            strongest 2023–2024 evidence supporting roles in **AMPAR (GluA2/3)
            internalization/recycling and synaptic plasticity** through phosphorylation-dependent
            partner switching and regulated complex formation.
  - term:
      id: GO:0014069
      label: postsynaptic density
    evidence_type: IEA
    original_reference_id: GO_REF:0000044
    review:
      summary: Postsynaptic density localization is supported by PICK1 action at postsynaptic AMPAR
        complexes.
      action: ACCEPT
      reason: postsynaptic density is supported as part of PICK1 PDZ/BAR scaffold,
        membrane-remodeling, or synaptic receptor-trafficking function.
      supported_by:
        - reference_id: file:human/PICK1/PICK1-deep-research-falcon.md
          supporting_text: PICK1 is described as enriched in brain and localized to **pre- and
            postsynaptic compartments**, consistent with its role in regulating synaptic receptor
            trafficking
        - reference_id: file:human/PICK1/PICK1-deep-research-falcon.md
          supporting_text: Across the recent literature, PICK1’s primary molecular role is best
            described as a **PDZ/BAR scaffold that regulates the trafficking and surface
            availability of membrane proteins—especially AMPA-type glutamate receptors—by
            coordinating protein complex assembly with membrane remodeling and endocytic/recycling
            processes**
  - term:
      id: GO:0016020
      label: membrane
    evidence_type: IEA
    original_reference_id: GO_REF:0000044
    review:
      summary: membrane is plausible as a context-specific PICK1 localization, binding, or
        downstream process, but it is secondary to the core PDZ/BAR receptor-trafficking function.
      action: KEEP_AS_NON_CORE
      reason: membrane is secondary to PICK1 membrane protein trafficking and synaptic receptor
        organization.
      supported_by:
        - reference_id: file:human/PICK1/PICK1-deep-research-falcon.md
          supporting_text: Across the recent literature, PICK1’s primary molecular role is best
            described as a **PDZ/BAR scaffold that regulates the trafficking and surface
            availability of membrane proteins—especially AMPA-type glutamate receptors—by
            coordinating protein complex assembly with membrane remodeling and endocytic/recycling
            processes**
        - reference_id: file:human/PICK1/PICK1-deep-research-falcon.md
          supporting_text: Human **PICK1 (Q9NRD5)** is best annotated as a **PDZ/BAR scaffolding and
            membrane-remodeling protein** that controls **membrane protein trafficking**, with the
            strongest 2023–2024 evidence supporting roles in **AMPAR (GluA2/3)
            internalization/recycling and synaptic plasticity** through phosphorylation-dependent
            partner switching and regulated complex formation.
  - term:
      id: GO:0019904
      label: protein domain specific binding
    evidence_type: IEA
    original_reference_id: GO_REF:0000002
    review:
      summary: Protein domain specific binding is supported by PICK1 PDZ-domain recognition of
        receptor/cargo C-terminal motifs.
      action: ACCEPT
      reason: protein domain specific binding is supported as part of PICK1 PDZ/BAR scaffold,
        membrane-remodeling, or synaptic receptor-trafficking function.
      supported_by:
        - reference_id: file:human/PICK1/PICK1-deep-research-falcon.md
          supporting_text: '**PDZ domain (protein interaction module):** In AMPAR biology, authoritative
            review evidence states that the **GluA2 C-terminus** contains a PDZ ligand that binds directly
            to **PICK1** (and GRIP1), and that PICK1 binds GluA2 via its PDZ domain'
  - term:
      id: GO:0043005
      label: neuron projection
    evidence_type: IEA
    original_reference_id: GO_REF:0000043
    review:
      summary: Neuron projection localization is consistent with PICK1 function in pre- and
        postsynaptic neuronal compartments.
      action: ACCEPT
      reason: neuron projection is supported as part of PICK1 PDZ/BAR scaffold, membrane-remodeling,
        or synaptic receptor-trafficking function.
      supported_by:
        - reference_id: file:human/PICK1/PICK1-deep-research-falcon.md
          supporting_text: PICK1 is described as enriched in brain and localized to **pre- and
            postsynaptic compartments**, consistent with its role in regulating synaptic receptor
            trafficking
  - term:
      id: GO:0045202
      label: synapse
    evidence_type: IEA
    original_reference_id: GO_REF:0000120
    review:
      summary: Synapse localization is supported by PICK1 enrichment in pre- and postsynaptic
        compartments.
      action: ACCEPT
      reason: synapse is supported as part of PICK1 PDZ/BAR scaffold, membrane-remodeling, or
        synaptic receptor-trafficking function.
      supported_by:
        - reference_id: file:human/PICK1/PICK1-deep-research-falcon.md
          supporting_text: PICK1 is described as enriched in brain and localized to **pre- and
            postsynaptic compartments**, consistent with its role in regulating synaptic receptor
            trafficking
  - term:
      id: GO:0046872
      label: metal ion binding
    evidence_type: IEA
    original_reference_id: GO_REF:0000043
    review:
      summary: Metal ion binding is not the functionally informative annotation for PICK1 compared
        with PDZ/BAR scaffold and membrane-remodeling activities.
      action: MARK_AS_OVER_ANNOTATED
      reason: metal ion binding is less informative than the specific PICK1 scaffold mechanism.
      supported_by:
        - reference_id: file:human/PICK1/PICK1-deep-research-falcon.md
          supporting_text: '**PICK1 is a dual-domain scaffolding/adaptor protein** that couples (i) **PDZ-domain–mediated
            binding** to C-terminal motifs on cargo proteins with (ii) **BAR/N‑BAR–mediated lipid/membrane
            binding and remodeling**, enabling regulation of membrane protein trafficking and compartmentalization'
  - term:
      id: GO:0048471
      label: perinuclear region of cytoplasm
    evidence_type: IEA
    original_reference_id: GO_REF:0000044
    review:
      summary: perinuclear region of cytoplasm is plausible as a context-specific PICK1
        localization, binding, or downstream process, but it is secondary to the core PDZ/BAR
        receptor-trafficking function.
      action: KEEP_AS_NON_CORE
      reason: perinuclear region of cytoplasm is secondary to PICK1 membrane protein trafficking and
        synaptic receptor organization.
      supported_by:
        - reference_id: file:human/PICK1/PICK1-deep-research-falcon.md
          supporting_text: A 2024 Molecular Biology of the Cell study reports that in nonpolarized
            cells PICK1 is typically **cytosolic**, but under **sodium arsenite** stress it
            relocalizes to **perinuclear aggresomes**, identifying PICK1 as a stress-responsive
            organizer of protein sequestration/aggregation compartments
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:11343649
    review:
      summary: Protein binding is too generic for PICK1; PDZ-domain binding, PKC binding, receptor
        binding, and identical protein binding are more informative.
      action: MARK_AS_OVER_ANNOTATED
      reason: protein binding is less informative than the specific PICK1 scaffold mechanism.
      supported_by:
        - reference_id: file:human/PICK1/PICK1-deep-research-falcon.md
          supporting_text: '**PICK1 is a dual-domain scaffolding/adaptor protein** that couples (i) **PDZ-domain–mediated
            binding** to C-terminal motifs on cargo proteins with (ii) **BAR/N‑BAR–mediated lipid/membrane
            binding and remodeling**, enabling regulation of membrane protein trafficking and compartmentalization'
        - reference_id: file:human/PICK1/PICK1-deep-research-falcon.md
          supporting_text: '**PDZ domain (protein interaction module):** In AMPAR biology, authoritative
            review evidence states that the **GluA2 C-terminus** contains a PDZ ligand that binds directly
            to **PICK1** (and GRIP1), and that PICK1 binds GluA2 via its PDZ domain'
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:11802773
    review:
      summary: Protein binding is too generic for PICK1; PDZ-domain binding, PKC binding, receptor
        binding, and identical protein binding are more informative.
      action: MARK_AS_OVER_ANNOTATED
      reason: protein binding is less informative than the specific PICK1 scaffold mechanism.
      supported_by:
        - reference_id: file:human/PICK1/PICK1-deep-research-falcon.md
          supporting_text: '**PICK1 is a dual-domain scaffolding/adaptor protein** that couples (i) **PDZ-domain–mediated
            binding** to C-terminal motifs on cargo proteins with (ii) **BAR/N‑BAR–mediated lipid/membrane
            binding and remodeling**, enabling regulation of membrane protein trafficking and compartmentalization'
        - reference_id: file:human/PICK1/PICK1-deep-research-falcon.md
          supporting_text: '**PDZ domain (protein interaction module):** In AMPAR biology, authoritative
            review evidence states that the **GluA2 C-terminus** contains a PDZ ligand that binds directly
            to **PICK1** (and GRIP1), and that PICK1 binds GluA2 via its PDZ domain'
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:16713569
    review:
      summary: Protein binding is too generic for PICK1; PDZ-domain binding, PKC binding, receptor
        binding, and identical protein binding are more informative.
      action: MARK_AS_OVER_ANNOTATED
      reason: protein binding is less informative than the specific PICK1 scaffold mechanism.
      supported_by:
        - reference_id: file:human/PICK1/PICK1-deep-research-falcon.md
          supporting_text: '**PICK1 is a dual-domain scaffolding/adaptor protein** that couples (i) **PDZ-domain–mediated
            binding** to C-terminal motifs on cargo proteins with (ii) **BAR/N‑BAR–mediated lipid/membrane
            binding and remodeling**, enabling regulation of membrane protein trafficking and compartmentalization'
        - reference_id: file:human/PICK1/PICK1-deep-research-falcon.md
          supporting_text: '**PDZ domain (protein interaction module):** In AMPAR biology, authoritative
            review evidence states that the **GluA2 C-terminus** contains a PDZ ligand that binds directly
            to **PICK1** (and GRIP1), and that PICK1 binds GluA2 via its PDZ domain'
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:21653829
    review:
      summary: Protein binding is too generic for PICK1; PDZ-domain binding, PKC binding, receptor
        binding, and identical protein binding are more informative.
      action: MARK_AS_OVER_ANNOTATED
      reason: protein binding is less informative than the specific PICK1 scaffold mechanism.
      supported_by:
        - reference_id: file:human/PICK1/PICK1-deep-research-falcon.md
          supporting_text: '**PICK1 is a dual-domain scaffolding/adaptor protein** that couples (i) **PDZ-domain–mediated
            binding** to C-terminal motifs on cargo proteins with (ii) **BAR/N‑BAR–mediated lipid/membrane
            binding and remodeling**, enabling regulation of membrane protein trafficking and compartmentalization'
        - reference_id: file:human/PICK1/PICK1-deep-research-falcon.md
          supporting_text: '**PDZ domain (protein interaction module):** In AMPAR biology, authoritative
            review evidence states that the **GluA2 C-terminus** contains a PDZ ligand that binds directly
            to **PICK1** (and GRIP1), and that PICK1 binds GluA2 via its PDZ domain'
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:26787460
    review:
      summary: Protein binding is too generic for PICK1; PDZ-domain binding, PKC binding, receptor
        binding, and identical protein binding are more informative.
      action: MARK_AS_OVER_ANNOTATED
      reason: protein binding is less informative than the specific PICK1 scaffold mechanism.
      supported_by:
        - reference_id: file:human/PICK1/PICK1-deep-research-falcon.md
          supporting_text: '**PICK1 is a dual-domain scaffolding/adaptor protein** that couples (i) **PDZ-domain–mediated
            binding** to C-terminal motifs on cargo proteins with (ii) **BAR/N‑BAR–mediated lipid/membrane
            binding and remodeling**, enabling regulation of membrane protein trafficking and compartmentalization'
        - reference_id: file:human/PICK1/PICK1-deep-research-falcon.md
          supporting_text: '**PDZ domain (protein interaction module):** In AMPAR biology, authoritative
            review evidence states that the **GluA2 C-terminus** contains a PDZ ligand that binds directly
            to **PICK1** (and GRIP1), and that PICK1 binds GluA2 via its PDZ domain'
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:28514442
    review:
      summary: Protein binding is too generic for PICK1; PDZ-domain binding, PKC binding, receptor
        binding, and identical protein binding are more informative.
      action: MARK_AS_OVER_ANNOTATED
      reason: protein binding is less informative than the specific PICK1 scaffold mechanism.
      supported_by:
        - reference_id: file:human/PICK1/PICK1-deep-research-falcon.md
          supporting_text: '**PICK1 is a dual-domain scaffolding/adaptor protein** that couples (i) **PDZ-domain–mediated
            binding** to C-terminal motifs on cargo proteins with (ii) **BAR/N‑BAR–mediated lipid/membrane
            binding and remodeling**, enabling regulation of membrane protein trafficking and compartmentalization'
        - reference_id: file:human/PICK1/PICK1-deep-research-falcon.md
          supporting_text: '**PDZ domain (protein interaction module):** In AMPAR biology, authoritative
            review evidence states that the **GluA2 C-terminus** contains a PDZ ligand that binds directly
            to **PICK1** (and GRIP1), and that PICK1 binds GluA2 via its PDZ domain'
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:31413325
    review:
      summary: Protein binding is too generic for PICK1; PDZ-domain binding, PKC binding, receptor
        binding, and identical protein binding are more informative.
      action: MARK_AS_OVER_ANNOTATED
      reason: protein binding is less informative than the specific PICK1 scaffold mechanism.
      supported_by:
        - reference_id: file:human/PICK1/PICK1-deep-research-falcon.md
          supporting_text: '**PICK1 is a dual-domain scaffolding/adaptor protein** that couples (i) **PDZ-domain–mediated
            binding** to C-terminal motifs on cargo proteins with (ii) **BAR/N‑BAR–mediated lipid/membrane
            binding and remodeling**, enabling regulation of membrane protein trafficking and compartmentalization'
        - reference_id: file:human/PICK1/PICK1-deep-research-falcon.md
          supporting_text: '**PDZ domain (protein interaction module):** In AMPAR biology, authoritative
            review evidence states that the **GluA2 C-terminus** contains a PDZ ligand that binds directly
            to **PICK1** (and GRIP1), and that PICK1 binds GluA2 via its PDZ domain'
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:32296183
    review:
      summary: Protein binding is too generic for PICK1; PDZ-domain binding, PKC binding, receptor
        binding, and identical protein binding are more informative.
      action: MARK_AS_OVER_ANNOTATED
      reason: protein binding is less informative than the specific PICK1 scaffold mechanism.
      supported_by:
        - reference_id: file:human/PICK1/PICK1-deep-research-falcon.md
          supporting_text: '**PICK1 is a dual-domain scaffolding/adaptor protein** that couples (i) **PDZ-domain–mediated
            binding** to C-terminal motifs on cargo proteins with (ii) **BAR/N‑BAR–mediated lipid/membrane
            binding and remodeling**, enabling regulation of membrane protein trafficking and compartmentalization'
        - reference_id: file:human/PICK1/PICK1-deep-research-falcon.md
          supporting_text: '**PDZ domain (protein interaction module):** In AMPAR biology, authoritative
            review evidence states that the **GluA2 C-terminus** contains a PDZ ligand that binds directly
            to **PICK1** (and GRIP1), and that PICK1 binds GluA2 via its PDZ domain'
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:32814053
    review:
      summary: Protein binding is too generic for PICK1; PDZ-domain binding, PKC binding, receptor
        binding, and identical protein binding are more informative.
      action: MARK_AS_OVER_ANNOTATED
      reason: protein binding is less informative than the specific PICK1 scaffold mechanism.
      supported_by:
        - reference_id: file:human/PICK1/PICK1-deep-research-falcon.md
          supporting_text: '**PICK1 is a dual-domain scaffolding/adaptor protein** that couples (i) **PDZ-domain–mediated
            binding** to C-terminal motifs on cargo proteins with (ii) **BAR/N‑BAR–mediated lipid/membrane
            binding and remodeling**, enabling regulation of membrane protein trafficking and compartmentalization'
        - reference_id: file:human/PICK1/PICK1-deep-research-falcon.md
          supporting_text: '**PDZ domain (protein interaction module):** In AMPAR biology, authoritative
            review evidence states that the **GluA2 C-terminus** contains a PDZ ligand that binds directly
            to **PICK1** (and GRIP1), and that PICK1 binds GluA2 via its PDZ domain'
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:33961781
    review:
      summary: Protein binding is too generic for PICK1; PDZ-domain binding, PKC binding, receptor
        binding, and identical protein binding are more informative.
      action: MARK_AS_OVER_ANNOTATED
      reason: protein binding is less informative than the specific PICK1 scaffold mechanism.
      supported_by:
        - reference_id: file:human/PICK1/PICK1-deep-research-falcon.md
          supporting_text: '**PICK1 is a dual-domain scaffolding/adaptor protein** that couples (i) **PDZ-domain–mediated
            binding** to C-terminal motifs on cargo proteins with (ii) **BAR/N‑BAR–mediated lipid/membrane
            binding and remodeling**, enabling regulation of membrane protein trafficking and compartmentalization'
        - reference_id: file:human/PICK1/PICK1-deep-research-falcon.md
          supporting_text: '**PDZ domain (protein interaction module):** In AMPAR biology, authoritative
            review evidence states that the **GluA2 C-terminus** contains a PDZ ligand that binds directly
            to **PICK1** (and GRIP1), and that PICK1 binds GluA2 via its PDZ domain'
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:36115835
    review:
      summary: Protein binding is too generic for PICK1; PDZ-domain binding, PKC binding, receptor
        binding, and identical protein binding are more informative.
      action: MARK_AS_OVER_ANNOTATED
      reason: protein binding is less informative than the specific PICK1 scaffold mechanism.
      supported_by:
        - reference_id: file:human/PICK1/PICK1-deep-research-falcon.md
          supporting_text: '**PICK1 is a dual-domain scaffolding/adaptor protein** that couples (i) **PDZ-domain–mediated
            binding** to C-terminal motifs on cargo proteins with (ii) **BAR/N‑BAR–mediated lipid/membrane
            binding and remodeling**, enabling regulation of membrane protein trafficking and compartmentalization'
        - reference_id: file:human/PICK1/PICK1-deep-research-falcon.md
          supporting_text: '**PDZ domain (protein interaction module):** In AMPAR biology, authoritative
            review evidence states that the **GluA2 C-terminus** contains a PDZ ligand that binds directly
            to **PICK1** (and GRIP1), and that PICK1 binds GluA2 via its PDZ domain'
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:37207277
    review:
      summary: Protein binding is too generic for PICK1; PDZ-domain binding, PKC binding, receptor
        binding, and identical protein binding are more informative.
      action: MARK_AS_OVER_ANNOTATED
      reason: protein binding is less informative than the specific PICK1 scaffold mechanism.
      supported_by:
        - reference_id: file:human/PICK1/PICK1-deep-research-falcon.md
          supporting_text: '**PICK1 is a dual-domain scaffolding/adaptor protein** that couples (i) **PDZ-domain–mediated
            binding** to C-terminal motifs on cargo proteins with (ii) **BAR/N‑BAR–mediated lipid/membrane
            binding and remodeling**, enabling regulation of membrane protein trafficking and compartmentalization'
        - reference_id: file:human/PICK1/PICK1-deep-research-falcon.md
          supporting_text: '**PDZ domain (protein interaction module):** In AMPAR biology, authoritative
            review evidence states that the **GluA2 C-terminus** contains a PDZ ligand that binds directly
            to **PICK1** (and GRIP1), and that PICK1 binds GluA2 via its PDZ domain'
  - term:
      id: GO:0042802
      label: identical protein binding
    evidence_type: IPI
    original_reference_id: PMID:32296183
    review:
      summary: Identical protein binding is supported by BAR-domain homodimerization and
        higher-order PICK1 assembly.
      action: ACCEPT
      reason: identical protein binding is supported as part of PICK1 PDZ/BAR scaffold,
        membrane-remodeling, or synaptic receptor-trafficking function.
      supported_by:
        - reference_id: file:human/PICK1/PICK1-deep-research-falcon.md
          supporting_text: '**BAR / N‑BAR domain (membrane remodeling module):** BAR domains are classically
            crescent-shaped, lipid-binding modules involved in membrane curvature during trafficking.'
  - term:
      id: GO:0005829
      label: cytosol
    evidence_type: IDA
    original_reference_id: GO_REF:0000052
    review:
      summary: cytosol is plausible as a context-specific PICK1 localization, binding, or downstream
        process, but it is secondary to the core PDZ/BAR receptor-trafficking function.
      action: KEEP_AS_NON_CORE
      reason: cytosol is secondary to PICK1 membrane protein trafficking and synaptic receptor
        organization.
      supported_by:
        - reference_id: file:human/PICK1/PICK1-deep-research-falcon.md
          supporting_text: A 2024 Molecular Biology of the Cell study reports that in nonpolarized
            cells PICK1 is typically **cytosolic**, but under **sodium arsenite** stress it
            relocalizes to **perinuclear aggresomes**, identifying PICK1 as a stress-responsive
            organizer of protein sequestration/aggregation compartments
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:16314870
    review:
      summary: Protein binding is too generic for PICK1; PDZ-domain binding, PKC binding, receptor
        binding, and identical protein binding are more informative.
      action: MARK_AS_OVER_ANNOTATED
      reason: protein binding is less informative than the specific PICK1 scaffold mechanism.
      supported_by:
        - reference_id: file:human/PICK1/PICK1-deep-research-falcon.md
          supporting_text: '**PICK1 is a dual-domain scaffolding/adaptor protein** that couples (i) **PDZ-domain–mediated
            binding** to C-terminal motifs on cargo proteins with (ii) **BAR/N‑BAR–mediated lipid/membrane
            binding and remodeling**, enabling regulation of membrane protein trafficking and compartmentalization'
        - reference_id: file:human/PICK1/PICK1-deep-research-falcon.md
          supporting_text: '**PDZ domain (protein interaction module):** In AMPAR biology, authoritative
            review evidence states that the **GluA2 C-terminus** contains a PDZ ligand that binds directly
            to **PICK1** (and GRIP1), and that PICK1 binds GluA2 via its PDZ domain'
  - term:
      id: GO:0050796
      label: regulation of insulin secretion
    evidence_type: IMP
    original_reference_id: PMID:29768204
    review:
      summary: regulation of insulin secretion is plausible as a context-specific PICK1
        localization, binding, or downstream process, but it is secondary to the core PDZ/BAR
        receptor-trafficking function.
      action: KEEP_AS_NON_CORE
      reason: regulation of insulin secretion is secondary to PICK1 membrane protein trafficking and
        synaptic receptor organization.
      supported_by:
        - reference_id: file:human/PICK1/PICK1-deep-research-falcon.md
          supporting_text: Across the recent literature, PICK1’s primary molecular role is best
            described as a **PDZ/BAR scaffold that regulates the trafficking and surface
            availability of membrane proteins—especially AMPA-type glutamate receptors—by
            coordinating protein complex assembly with membrane remodeling and endocytic/recycling
            processes**
        - reference_id: file:human/PICK1/PICK1-deep-research-falcon.md
          supporting_text: Human **PICK1 (Q9NRD5)** is best annotated as a **PDZ/BAR scaffolding and
            membrane-remodeling protein** that controls **membrane protein trafficking**, with the
            strongest 2023–2024 evidence supporting roles in **AMPAR (GluA2/3)
            internalization/recycling and synaptic plasticity** through phosphorylation-dependent
            partner switching and regulated complex formation.
  - term:
      id: GO:0140090
      label: membrane curvature sensor activity
    evidence_type: IDA
    original_reference_id: PMID:29768204
    review:
      summary: Membrane curvature sensor activity is supported by PICK1 BAR/N-BAR
        membrane-remodeling function.
      action: ACCEPT
      reason: membrane curvature sensor activity is supported as part of PICK1 PDZ/BAR scaffold,
        membrane-remodeling, or synaptic receptor-trafficking function.
      supported_by:
        - reference_id: file:human/PICK1/PICK1-deep-research-falcon.md
          supporting_text: '**BAR / N‑BAR domain (membrane remodeling module):** BAR domains are classically
            crescent-shaped, lipid-binding modules involved in membrane curvature during trafficking.'
        - reference_id: file:human/PICK1/PICK1-deep-research-falcon.md
          supporting_text: '**PICK1 is a dual-domain scaffolding/adaptor protein** that couples (i) **PDZ-domain–mediated
            binding** to C-terminal motifs on cargo proteins with (ii) **BAR/N‑BAR–mediated lipid/membrane
            binding and remodeling**, enabling regulation of membrane protein trafficking and compartmentalization'
  - term:
      id: GO:0001664
      label: G protein-coupled receptor binding
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    review:
      summary: G protein-coupled receptor binding is plausible as a context-specific PICK1
        localization, binding, or downstream process, but it is secondary to the core PDZ/BAR
        receptor-trafficking function.
      action: KEEP_AS_NON_CORE
      reason: G protein-coupled receptor binding is secondary to PICK1 membrane protein trafficking
        and synaptic receptor organization.
      supported_by:
        - reference_id: file:human/PICK1/PICK1-deep-research-falcon.md
          supporting_text: Across the recent literature, PICK1’s primary molecular role is best
            described as a **PDZ/BAR scaffold that regulates the trafficking and surface
            availability of membrane proteins—especially AMPA-type glutamate receptors—by
            coordinating protein complex assembly with membrane remodeling and endocytic/recycling
            processes**
        - reference_id: file:human/PICK1/PICK1-deep-research-falcon.md
          supporting_text: Human **PICK1 (Q9NRD5)** is best annotated as a **PDZ/BAR scaffolding and
            membrane-remodeling protein** that controls **membrane protein trafficking**, with the
            strongest 2023–2024 evidence supporting roles in **AMPAR (GluA2/3)
            internalization/recycling and synaptic plasticity** through phosphorylation-dependent
            partner switching and regulated complex formation.
  - term:
      id: GO:0019904
      label: protein domain specific binding
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    review:
      summary: Protein domain specific binding is supported by PICK1 PDZ-domain recognition of
        receptor/cargo C-terminal motifs.
      action: ACCEPT
      reason: protein domain specific binding is supported as part of PICK1 PDZ/BAR scaffold,
        membrane-remodeling, or synaptic receptor-trafficking function.
      supported_by:
        - reference_id: file:human/PICK1/PICK1-deep-research-falcon.md
          supporting_text: '**PDZ domain (protein interaction module):** In AMPAR biology, authoritative
            review evidence states that the **GluA2 C-terminus** contains a PDZ ligand that binds directly
            to **PICK1** (and GRIP1), and that PICK1 binds GluA2 via its PDZ domain'
  - term:
      id: GO:0042802
      label: identical protein binding
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    review:
      summary: Identical protein binding is supported by BAR-domain homodimerization and
        higher-order PICK1 assembly.
      action: ACCEPT
      reason: identical protein binding is supported as part of PICK1 PDZ/BAR scaffold,
        membrane-remodeling, or synaptic receptor-trafficking function.
      supported_by:
        - reference_id: file:human/PICK1/PICK1-deep-research-falcon.md
          supporting_text: '**BAR / N‑BAR domain (membrane remodeling module):** BAR domains are classically
            crescent-shaped, lipid-binding modules involved in membrane curvature during trafficking.'
  - term:
      id: GO:0002092
      label: positive regulation of receptor internalization
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    review:
      summary: Positive regulation of receptor internalization is a core PICK1-supported process for
        AMPAR GluA2 trafficking.
      action: ACCEPT
      reason: positive regulation of receptor internalization is supported as part of PICK1 PDZ/BAR
        scaffold, membrane-remodeling, or synaptic receptor-trafficking function.
      supported_by:
        - reference_id: file:human/PICK1/PICK1-deep-research-falcon.md
          supporting_text: In vivo evidence from mouse hippocampus (kainic acid model) supports a
            mechanistic switch in which **GluA2 Ser880 phosphorylation** promotes dissociation from
            GRIP1 and association with PICK1, driving AMPAR endocytosis/internalization;
            PP2A-mediated dephosphorylation reverses this and disfavors PICK1 association
        - reference_id: file:human/PICK1/PICK1-deep-research-falcon.md
          supporting_text: Across the recent literature, PICK1’s primary molecular role is best
            described as a **PDZ/BAR scaffold that regulates the trafficking and surface
            availability of membrane proteins—especially AMPA-type glutamate receptors—by
            coordinating protein complex assembly with membrane remodeling and endocytic/recycling
            processes**
  - term:
      id: GO:0021782
      label: glial cell development
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    review:
      summary: glial cell development is plausible as a context-specific PICK1 localization,
        binding, or downstream process, but it is secondary to the core PDZ/BAR receptor-trafficking
        function.
      action: KEEP_AS_NON_CORE
      reason: glial cell development is secondary to PICK1 membrane protein trafficking and synaptic
        receptor organization.
      supported_by:
        - reference_id: file:human/PICK1/PICK1-deep-research-falcon.md
          supporting_text: Across the recent literature, PICK1’s primary molecular role is best
            described as a **PDZ/BAR scaffold that regulates the trafficking and surface
            availability of membrane proteins—especially AMPA-type glutamate receptors—by
            coordinating protein complex assembly with membrane remodeling and endocytic/recycling
            processes**
        - reference_id: file:human/PICK1/PICK1-deep-research-falcon.md
          supporting_text: Human **PICK1 (Q9NRD5)** is best annotated as a **PDZ/BAR scaffolding and
            membrane-remodeling protein** that controls **membrane protein trafficking**, with the
            strongest 2023–2024 evidence supporting roles in **AMPAR (GluA2/3)
            internalization/recycling and synaptic plasticity** through phosphorylation-dependent
            partner switching and regulated complex formation.
  - term:
      id: GO:0034316
      label: negative regulation of Arp2/3 complex-mediated actin nucleation
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    review:
      summary: negative regulation of Arp2/3 complex-mediated actin nucleation is plausible as a
        context-specific PICK1 localization, binding, or downstream process, but it is secondary to
        the core PDZ/BAR receptor-trafficking function.
      action: KEEP_AS_NON_CORE
      reason: negative regulation of Arp2/3 complex-mediated actin nucleation is secondary to PICK1
        membrane protein trafficking and synaptic receptor organization.
      supported_by:
        - reference_id: file:human/PICK1/PICK1-deep-research-falcon.md
          supporting_text: Across the recent literature, PICK1’s primary molecular role is best
            described as a **PDZ/BAR scaffold that regulates the trafficking and surface
            availability of membrane proteins—especially AMPA-type glutamate receptors—by
            coordinating protein complex assembly with membrane remodeling and endocytic/recycling
            processes**
        - reference_id: file:human/PICK1/PICK1-deep-research-falcon.md
          supporting_text: Human **PICK1 (Q9NRD5)** is best annotated as a **PDZ/BAR scaffolding and
            membrane-remodeling protein** that controls **membrane protein trafficking**, with the
            strongest 2023–2024 evidence supporting roles in **AMPAR (GluA2/3)
            internalization/recycling and synaptic plasticity** through phosphorylation-dependent
            partner switching and regulated complex formation.
  - term:
      id: GO:0036294
      label: cellular response to decreased oxygen levels
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    review:
      summary: cellular response to decreased oxygen levels is plausible as a context-specific PICK1
        localization, binding, or downstream process, but it is secondary to the core PDZ/BAR
        receptor-trafficking function.
      action: KEEP_AS_NON_CORE
      reason: cellular response to decreased oxygen levels is secondary to PICK1 membrane protein
        trafficking and synaptic receptor organization.
      supported_by:
        - reference_id: file:human/PICK1/PICK1-deep-research-falcon.md
          supporting_text: Across the recent literature, PICK1’s primary molecular role is best
            described as a **PDZ/BAR scaffold that regulates the trafficking and surface
            availability of membrane proteins—especially AMPA-type glutamate receptors—by
            coordinating protein complex assembly with membrane remodeling and endocytic/recycling
            processes**
        - reference_id: file:human/PICK1/PICK1-deep-research-falcon.md
          supporting_text: Human **PICK1 (Q9NRD5)** is best annotated as a **PDZ/BAR scaffolding and
            membrane-remodeling protein** that controls **membrane protein trafficking**, with the
            strongest 2023–2024 evidence supporting roles in **AMPAR (GluA2/3)
            internalization/recycling and synaptic plasticity** through phosphorylation-dependent
            partner switching and regulated complex formation.
  - term:
      id: GO:0042149
      label: cellular response to glucose starvation
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    review:
      summary: cellular response to glucose starvation is plausible as a context-specific PICK1
        localization, binding, or downstream process, but it is secondary to the core PDZ/BAR
        receptor-trafficking function.
      action: KEEP_AS_NON_CORE
      reason: cellular response to glucose starvation is secondary to PICK1 membrane protein
        trafficking and synaptic receptor organization.
      supported_by:
        - reference_id: file:human/PICK1/PICK1-deep-research-falcon.md
          supporting_text: Across the recent literature, PICK1’s primary molecular role is best
            described as a **PDZ/BAR scaffold that regulates the trafficking and surface
            availability of membrane proteins—especially AMPA-type glutamate receptors—by
            coordinating protein complex assembly with membrane remodeling and endocytic/recycling
            processes**
        - reference_id: file:human/PICK1/PICK1-deep-research-falcon.md
          supporting_text: Human **PICK1 (Q9NRD5)** is best annotated as a **PDZ/BAR scaffolding and
            membrane-remodeling protein** that controls **membrane protein trafficking**, with the
            strongest 2023–2024 evidence supporting roles in **AMPAR (GluA2/3)
            internalization/recycling and synaptic plasticity** through phosphorylation-dependent
            partner switching and regulated complex formation.
  - term:
      id: GO:0043005
      label: neuron projection
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    review:
      summary: Neuron projection localization is consistent with PICK1 function in pre- and
        postsynaptic neuronal compartments.
      action: ACCEPT
      reason: neuron projection is supported as part of PICK1 PDZ/BAR scaffold, membrane-remodeling,
        or synaptic receptor-trafficking function.
      supported_by:
        - reference_id: file:human/PICK1/PICK1-deep-research-falcon.md
          supporting_text: PICK1 is described as enriched in brain and localized to **pre- and
            postsynaptic compartments**, consistent with its role in regulating synaptic receptor
            trafficking
  - term:
      id: GO:0051015
      label: actin filament binding
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    review:
      summary: actin filament binding is plausible as a context-specific PICK1 localization,
        binding, or downstream process, but it is secondary to the core PDZ/BAR receptor-trafficking
        function.
      action: KEEP_AS_NON_CORE
      reason: actin filament binding is secondary to PICK1 membrane protein trafficking and synaptic
        receptor organization.
      supported_by:
        - reference_id: file:human/PICK1/PICK1-deep-research-falcon.md
          supporting_text: Across the recent literature, PICK1’s primary molecular role is best
            described as a **PDZ/BAR scaffold that regulates the trafficking and surface
            availability of membrane proteins—especially AMPA-type glutamate receptors—by
            coordinating protein complex assembly with membrane remodeling and endocytic/recycling
            processes**
        - reference_id: file:human/PICK1/PICK1-deep-research-falcon.md
          supporting_text: Human **PICK1 (Q9NRD5)** is best annotated as a **PDZ/BAR scaffolding and
            membrane-remodeling protein** that controls **membrane protein trafficking**, with the
            strongest 2023–2024 evidence supporting roles in **AMPAR (GluA2/3)
            internalization/recycling and synaptic plasticity** through phosphorylation-dependent
            partner switching and regulated complex formation.
  - term:
      id: GO:0060292
      label: long-term synaptic depression
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    review:
      summary: Long-term synaptic depression is supported as a synaptic plasticity context for
        PICK1-mediated AMPAR internalization.
      action: ACCEPT
      reason: long-term synaptic depression is supported as part of PICK1 PDZ/BAR scaffold,
        membrane-remodeling, or synaptic receptor-trafficking function.
      supported_by:
        - reference_id: file:human/PICK1/PICK1-deep-research-falcon.md
          supporting_text: In vivo evidence from mouse hippocampus (kainic acid model) supports a
            mechanistic switch in which **GluA2 Ser880 phosphorylation** promotes dissociation from
            GRIP1 and association with PICK1, driving AMPAR endocytosis/internalization;
            PP2A-mediated dephosphorylation reverses this and disfavors PICK1 association
        - reference_id: file:human/PICK1/PICK1-deep-research-falcon.md
          supporting_text: Human **PICK1 (Q9NRD5)** is best annotated as a **PDZ/BAR scaffolding and
            membrane-remodeling protein** that controls **membrane protein trafficking**, with the
            strongest 2023–2024 evidence supporting roles in **AMPAR (GluA2/3)
            internalization/recycling and synaptic plasticity** through phosphorylation-dependent
            partner switching and regulated complex formation.
  - term:
      id: GO:0071933
      label: Arp2/3 complex binding
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    review:
      summary: Arp2/3 complex binding is plausible as a context-specific PICK1 localization,
        binding, or downstream process, but it is secondary to the core PDZ/BAR receptor-trafficking
        function.
      action: KEEP_AS_NON_CORE
      reason: Arp2/3 complex binding is secondary to PICK1 membrane protein trafficking and synaptic
        receptor organization.
      supported_by:
        - reference_id: file:human/PICK1/PICK1-deep-research-falcon.md
          supporting_text: Across the recent literature, PICK1’s primary molecular role is best
            described as a **PDZ/BAR scaffold that regulates the trafficking and surface
            availability of membrane proteins—especially AMPA-type glutamate receptors—by
            coordinating protein complex assembly with membrane remodeling and endocytic/recycling
            processes**
        - reference_id: file:human/PICK1/PICK1-deep-research-falcon.md
          supporting_text: Human **PICK1 (Q9NRD5)** is best annotated as a **PDZ/BAR scaffolding and
            membrane-remodeling protein** that controls **membrane protein trafficking**, with the
            strongest 2023–2024 evidence supporting roles in **AMPAR (GluA2/3)
            internalization/recycling and synaptic plasticity** through phosphorylation-dependent
            partner switching and regulated complex formation.
  - term:
      id: GO:0097061
      label: dendritic spine organization
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    review:
      summary: Dendritic spine organization is supported through PICK1-dependent AMPAR trafficking
        and synaptic plasticity.
      action: ACCEPT
      reason: dendritic spine organization is supported as part of PICK1 PDZ/BAR scaffold,
        membrane-remodeling, or synaptic receptor-trafficking function.
      supported_by:
        - reference_id: file:human/PICK1/PICK1-deep-research-falcon.md
          supporting_text: Across the recent literature, PICK1’s primary molecular role is best
            described as a **PDZ/BAR scaffold that regulates the trafficking and surface
            availability of membrane proteins—especially AMPA-type glutamate receptors—by
            coordinating protein complex assembly with membrane remodeling and endocytic/recycling
            processes**
        - reference_id: file:human/PICK1/PICK1-deep-research-falcon.md
          supporting_text: PICK1 is described as enriched in brain and localized to **pre- and
            postsynaptic compartments**, consistent with its role in regulating synaptic receptor
            trafficking
  - term:
      id: GO:0097062
      label: dendritic spine maintenance
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    review:
      summary: Dendritic spine maintenance is supported by PICK1 roles in AMPAR trafficking and
        synaptic plasticity.
      action: ACCEPT
      reason: dendritic spine maintenance is supported as part of PICK1 PDZ/BAR scaffold,
        membrane-remodeling, or synaptic receptor-trafficking function.
      supported_by:
        - reference_id: file:human/PICK1/PICK1-deep-research-falcon.md
          supporting_text: Across the recent literature, PICK1’s primary molecular role is best
            described as a **PDZ/BAR scaffold that regulates the trafficking and surface
            availability of membrane proteins—especially AMPA-type glutamate receptors—by
            coordinating protein complex assembly with membrane remodeling and endocytic/recycling
            processes**
        - reference_id: file:human/PICK1/PICK1-deep-research-falcon.md
          supporting_text: PICK1 is described as enriched in brain and localized to **pre- and
            postsynaptic compartments**, consistent with its role in regulating synaptic receptor
            trafficking
  - term:
      id: GO:0005886
      label: plasma membrane
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-416639
    review:
      summary: Plasma membrane localization is supported by PICK1 roles in surface receptor
        internalization and trafficking.
      action: ACCEPT
      reason: plasma membrane is supported as part of PICK1 PDZ/BAR scaffold, membrane-remodeling,
        or synaptic receptor-trafficking function.
      supported_by:
        - reference_id: file:human/PICK1/PICK1-deep-research-falcon.md
          supporting_text: In vivo evidence from mouse hippocampus (kainic acid model) supports a
            mechanistic switch in which **GluA2 Ser880 phosphorylation** promotes dissociation from
            GRIP1 and association with PICK1, driving AMPAR endocytosis/internalization;
            PP2A-mediated dephosphorylation reverses this and disfavors PICK1 association
        - reference_id: file:human/PICK1/PICK1-deep-research-falcon.md
          supporting_text: Across the recent literature, PICK1’s primary molecular role is best
            described as a **PDZ/BAR scaffold that regulates the trafficking and surface
            availability of membrane proteins—especially AMPA-type glutamate receptors—by
            coordinating protein complex assembly with membrane remodeling and endocytic/recycling
            processes**
  - term:
      id: GO:0005886
      label: plasma membrane
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-416985
    review:
      summary: Plasma membrane localization is supported by PICK1 roles in surface receptor
        internalization and trafficking.
      action: ACCEPT
      reason: plasma membrane is supported as part of PICK1 PDZ/BAR scaffold, membrane-remodeling,
        or synaptic receptor-trafficking function.
      supported_by:
        - reference_id: file:human/PICK1/PICK1-deep-research-falcon.md
          supporting_text: In vivo evidence from mouse hippocampus (kainic acid model) supports a
            mechanistic switch in which **GluA2 Ser880 phosphorylation** promotes dissociation from
            GRIP1 and association with PICK1, driving AMPAR endocytosis/internalization;
            PP2A-mediated dephosphorylation reverses this and disfavors PICK1 association
        - reference_id: file:human/PICK1/PICK1-deep-research-falcon.md
          supporting_text: Across the recent literature, PICK1’s primary molecular role is best
            described as a **PDZ/BAR scaffold that regulates the trafficking and surface
            availability of membrane proteins—especially AMPA-type glutamate receptors—by
            coordinating protein complex assembly with membrane remodeling and endocytic/recycling
            processes**
  - term:
      id: GO:0005886
      label: plasma membrane
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-421007
    review:
      summary: Plasma membrane localization is supported by PICK1 roles in surface receptor
        internalization and trafficking.
      action: ACCEPT
      reason: plasma membrane is supported as part of PICK1 PDZ/BAR scaffold, membrane-remodeling,
        or synaptic receptor-trafficking function.
      supported_by:
        - reference_id: file:human/PICK1/PICK1-deep-research-falcon.md
          supporting_text: In vivo evidence from mouse hippocampus (kainic acid model) supports a
            mechanistic switch in which **GluA2 Ser880 phosphorylation** promotes dissociation from
            GRIP1 and association with PICK1, driving AMPAR endocytosis/internalization;
            PP2A-mediated dephosphorylation reverses this and disfavors PICK1 association
        - reference_id: file:human/PICK1/PICK1-deep-research-falcon.md
          supporting_text: Across the recent literature, PICK1’s primary molecular role is best
            described as a **PDZ/BAR scaffold that regulates the trafficking and surface
            availability of membrane proteins—especially AMPA-type glutamate receptors—by
            coordinating protein complex assembly with membrane remodeling and endocytic/recycling
            processes**
  - term:
      id: GO:0030666
      label: endocytic vesicle membrane
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-416639
    review:
      summary: Endocytic vesicle membrane localization is consistent with PICK1-mediated receptor
        internalization/recycling.
      action: ACCEPT
      reason: endocytic vesicle membrane is supported as part of PICK1 PDZ/BAR scaffold,
        membrane-remodeling, or synaptic receptor-trafficking function.
      supported_by:
        - reference_id: file:human/PICK1/PICK1-deep-research-falcon.md
          supporting_text: In vivo evidence from mouse hippocampus (kainic acid model) supports a
            mechanistic switch in which **GluA2 Ser880 phosphorylation** promotes dissociation from
            GRIP1 and association with PICK1, driving AMPAR endocytosis/internalization;
            PP2A-mediated dephosphorylation reverses this and disfavors PICK1 association
        - reference_id: file:human/PICK1/PICK1-deep-research-falcon.md
          supporting_text: Across the recent literature, PICK1’s primary molecular role is best
            described as a **PDZ/BAR scaffold that regulates the trafficking and surface
            availability of membrane proteins—especially AMPA-type glutamate receptors—by
            coordinating protein complex assembly with membrane remodeling and endocytic/recycling
            processes**
  - term:
      id: GO:0030666
      label: endocytic vesicle membrane
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-421007
    review:
      summary: Endocytic vesicle membrane localization is consistent with PICK1-mediated receptor
        internalization/recycling.
      action: ACCEPT
      reason: endocytic vesicle membrane is supported as part of PICK1 PDZ/BAR scaffold,
        membrane-remodeling, or synaptic receptor-trafficking function.
      supported_by:
        - reference_id: file:human/PICK1/PICK1-deep-research-falcon.md
          supporting_text: In vivo evidence from mouse hippocampus (kainic acid model) supports a
            mechanistic switch in which **GluA2 Ser880 phosphorylation** promotes dissociation from
            GRIP1 and association with PICK1, driving AMPAR endocytosis/internalization;
            PP2A-mediated dephosphorylation reverses this and disfavors PICK1 association
        - reference_id: file:human/PICK1/PICK1-deep-research-falcon.md
          supporting_text: Across the recent literature, PICK1’s primary molecular role is best
            described as a **PDZ/BAR scaffold that regulates the trafficking and surface
            availability of membrane proteins—especially AMPA-type glutamate receptors—by
            coordinating protein complex assembly with membrane remodeling and endocytic/recycling
            processes**
  - term:
      id: GO:0005737
      label: cytoplasm
    evidence_type: IDA
    original_reference_id: PMID:16314870
    review:
      summary: cytoplasm is plausible as a context-specific PICK1 localization, binding, or
        downstream process, but it is secondary to the core PDZ/BAR receptor-trafficking function.
      action: KEEP_AS_NON_CORE
      reason: cytoplasm is secondary to PICK1 membrane protein trafficking and synaptic receptor
        organization.
      supported_by:
        - reference_id: file:human/PICK1/PICK1-deep-research-falcon.md
          supporting_text: A 2024 Molecular Biology of the Cell study reports that in nonpolarized
            cells PICK1 is typically **cytosolic**, but under **sodium arsenite** stress it
            relocalizes to **perinuclear aggresomes**, identifying PICK1 as a stress-responsive
            organizer of protein sequestration/aggregation compartments
  - term:
      id: GO:0005102
      label: signaling receptor binding
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    review:
      summary: Signaling receptor binding is supported by PICK1 PDZ-domain interactions with
        receptor cargo such as AMPAR subunits.
      action: ACCEPT
      reason: signaling receptor binding is supported as part of PICK1 PDZ/BAR scaffold,
        membrane-remodeling, or synaptic receptor-trafficking function.
      supported_by:
        - reference_id: file:human/PICK1/PICK1-deep-research-falcon.md
          supporting_text: '**PDZ domain (protein interaction module):** In AMPAR biology, authoritative
            review evidence states that the **GluA2 C-terminus** contains a PDZ ligand that binds directly
            to **PICK1** (and GRIP1), and that PICK1 binds GluA2 via its PDZ domain'
        - reference_id: file:human/PICK1/PICK1-deep-research-falcon.md
          supporting_text: Across the recent literature, PICK1’s primary molecular role is best
            described as a **PDZ/BAR scaffold that regulates the trafficking and surface
            availability of membrane proteins—especially AMPA-type glutamate receptors—by
            coordinating protein complex assembly with membrane remodeling and endocytic/recycling
            processes**
  - term:
      id: GO:0043113
      label: receptor clustering
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    review:
      summary: Receptor clustering is supported by PICK1 PDZ/BAR-dependent organization of synaptic
        receptor complexes.
      action: ACCEPT
      reason: receptor clustering is supported as part of PICK1 PDZ/BAR scaffold,
        membrane-remodeling, or synaptic receptor-trafficking function.
      supported_by:
        - reference_id: file:human/PICK1/PICK1-deep-research-falcon.md
          supporting_text: Across the recent literature, PICK1’s primary molecular role is best
            described as a **PDZ/BAR scaffold that regulates the trafficking and surface
            availability of membrane proteins—especially AMPA-type glutamate receptors—by
            coordinating protein complex assembly with membrane remodeling and endocytic/recycling
            processes**
        - reference_id: file:human/PICK1/PICK1-deep-research-falcon.md
          supporting_text: '**PDZ domain (protein interaction module):** In AMPAR biology, authoritative
            review evidence states that the **GluA2 C-terminus** contains a PDZ ligand that binds directly
            to **PICK1** (and GRIP1), and that PICK1 binds GluA2 via its PDZ domain'
  - term:
      id: GO:0045202
      label: synapse
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    review:
      summary: Synapse localization is supported by PICK1 enrichment in pre- and postsynaptic
        compartments.
      action: ACCEPT
      reason: synapse is supported as part of PICK1 PDZ/BAR scaffold, membrane-remodeling, or
        synaptic receptor-trafficking function.
      supported_by:
        - reference_id: file:human/PICK1/PICK1-deep-research-falcon.md
          supporting_text: PICK1 is described as enriched in brain and localized to **pre- and
            postsynaptic compartments**, consistent with its role in regulating synaptic receptor
            trafficking
  - term:
      id: GO:0005080
      label: protein kinase C binding
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    review:
      summary: Protein kinase C binding is supported by PICK1 identity as a PKC-alpha-binding
        protein.
      action: ACCEPT
      reason: protein kinase C binding is supported as part of PICK1 PDZ/BAR scaffold,
        membrane-remodeling, or synaptic receptor-trafficking function.
      supported_by:
        - reference_id: file:human/PICK1/PICK1-deep-research-falcon.md
          supporting_text: PICK1 was originally cloned/recognized as a **PKCα-binding protein**, a
            point reiterated in 2023 work on synaptic receptor regulation
  - term:
      id: GO:0048471
      label: perinuclear region of cytoplasm
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    review:
      summary: perinuclear region of cytoplasm is plausible as a context-specific PICK1
        localization, binding, or downstream process, but it is secondary to the core PDZ/BAR
        receptor-trafficking function.
      action: KEEP_AS_NON_CORE
      reason: perinuclear region of cytoplasm is secondary to PICK1 membrane protein trafficking and
        synaptic receptor organization.
      supported_by:
        - reference_id: file:human/PICK1/PICK1-deep-research-falcon.md
          supporting_text: A 2024 Molecular Biology of the Cell study reports that in nonpolarized
            cells PICK1 is typically **cytosolic**, but under **sodium arsenite** stress it
            relocalizes to **perinuclear aggresomes**, identifying PICK1 as a stress-responsive
            organizer of protein sequestration/aggregation compartments
  - term:
      id: GO:0005794
      label: Golgi apparatus
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    review:
      summary: Golgi apparatus is plausible as a context-specific PICK1 localization, binding, or
        downstream process, but it is secondary to the core PDZ/BAR receptor-trafficking function.
      action: KEEP_AS_NON_CORE
      reason: Golgi apparatus is secondary to PICK1 membrane protein trafficking and synaptic
        receptor organization.
      supported_by:
        - reference_id: file:human/PICK1/PICK1-deep-research-falcon.md
          supporting_text: Across the recent literature, PICK1’s primary molecular role is best
            described as a **PDZ/BAR scaffold that regulates the trafficking and surface
            availability of membrane proteins—especially AMPA-type glutamate receptors—by
            coordinating protein complex assembly with membrane remodeling and endocytic/recycling
            processes**
        - reference_id: file:human/PICK1/PICK1-deep-research-falcon.md
          supporting_text: Human **PICK1 (Q9NRD5)** is best annotated as a **PDZ/BAR scaffolding and
            membrane-remodeling protein** that controls **membrane protein trafficking**, with the
            strongest 2023–2024 evidence supporting roles in **AMPAR (GluA2/3)
            internalization/recycling and synaptic plasticity** through phosphorylation-dependent
            partner switching and regulated complex formation.
  - term:
      id: GO:0006468
      label: protein phosphorylation
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    review:
      summary: PICK1 controls phosphorylation-dependent receptor partner switching as a scaffold,
        but it does not catalyze protein phosphorylation.
      action: REMOVE
      reason: PICK1 is a phosphorylation-dependent scaffold/trafficking regulator, not a kinase.
      supported_by:
        - reference_id: file:human/PICK1/PICK1-deep-research-falcon.md
          supporting_text: In vivo evidence from mouse hippocampus (kainic acid model) supports a
            mechanistic switch in which **GluA2 Ser880 phosphorylation** promotes dissociation from
            GRIP1 and association with PICK1, driving AMPAR endocytosis/internalization;
            PP2A-mediated dephosphorylation reverses this and disfavors PICK1 association
  - term:
      id: GO:0005737
      label: cytoplasm
    evidence_type: IDA
    original_reference_id: PMID:11343649
    review:
      summary: cytoplasm is plausible as a context-specific PICK1 localization, binding, or
        downstream process, but it is secondary to the core PDZ/BAR receptor-trafficking function.
      action: KEEP_AS_NON_CORE
      reason: cytoplasm is secondary to PICK1 membrane protein trafficking and synaptic receptor
        organization.
      supported_by:
        - reference_id: file:human/PICK1/PICK1-deep-research-falcon.md
          supporting_text: A 2024 Molecular Biology of the Cell study reports that in nonpolarized
            cells PICK1 is typically **cytosolic**, but under **sodium arsenite** stress it
            relocalizes to **perinuclear aggresomes**, identifying PICK1 as a stress-responsive
            organizer of protein sequestration/aggregation compartments
  - term:
      id: GO:0005886
      label: plasma membrane
    evidence_type: IDA
    original_reference_id: PMID:11343649
    review:
      summary: Plasma membrane localization is supported by PICK1 roles in surface receptor
        internalization and trafficking.
      action: ACCEPT
      reason: plasma membrane is supported as part of PICK1 PDZ/BAR scaffold, membrane-remodeling,
        or synaptic receptor-trafficking function.
      supported_by:
        - reference_id: file:human/PICK1/PICK1-deep-research-falcon.md
          supporting_text: In vivo evidence from mouse hippocampus (kainic acid model) supports a
            mechanistic switch in which **GluA2 Ser880 phosphorylation** promotes dissociation from
            GRIP1 and association with PICK1, driving AMPAR endocytosis/internalization;
            PP2A-mediated dephosphorylation reverses this and disfavors PICK1 association
        - reference_id: file:human/PICK1/PICK1-deep-research-falcon.md
          supporting_text: Across the recent literature, PICK1’s primary molecular role is best
            described as a **PDZ/BAR scaffold that regulates the trafficking and surface
            availability of membrane proteins—especially AMPA-type glutamate receptors—by
            coordinating protein complex assembly with membrane remodeling and endocytic/recycling
            processes**
  - term:
      id: GO:0015844
      label: monoamine transport
    evidence_type: IDA
    original_reference_id: PMID:11343649
    review:
      summary: monoamine transport is plausible as a context-specific PICK1 localization, binding,
        or downstream process, but it is secondary to the core PDZ/BAR receptor-trafficking
        function.
      action: KEEP_AS_NON_CORE
      reason: monoamine transport is secondary to PICK1 membrane protein trafficking and synaptic
        receptor organization.
      supported_by:
        - reference_id: file:human/PICK1/PICK1-deep-research-falcon.md
          supporting_text: Across the recent literature, PICK1’s primary molecular role is best
            described as a **PDZ/BAR scaffold that regulates the trafficking and surface
            availability of membrane proteins—especially AMPA-type glutamate receptors—by
            coordinating protein complex assembly with membrane remodeling and endocytic/recycling
            processes**
        - reference_id: file:human/PICK1/PICK1-deep-research-falcon.md
          supporting_text: Human **PICK1 (Q9NRD5)** is best annotated as a **PDZ/BAR scaffolding and
            membrane-remodeling protein** that controls **membrane protein trafficking**, with the
            strongest 2023–2024 evidence supporting roles in **AMPAR (GluA2/3)
            internalization/recycling and synaptic plasticity** through phosphorylation-dependent
            partner switching and regulated complex formation.
  - term:
      id: GO:0042734
      label: presynaptic membrane
    evidence_type: IDA
    original_reference_id: PMID:11343649
    review:
      summary: presynaptic membrane is plausible as a context-specific PICK1 localization, binding,
        or downstream process, but it is secondary to the core PDZ/BAR receptor-trafficking
        function.
      action: KEEP_AS_NON_CORE
      reason: presynaptic membrane is secondary to PICK1 membrane protein trafficking and synaptic
        receptor organization.
      supported_by:
        - reference_id: file:human/PICK1/PICK1-deep-research-falcon.md
          supporting_text: Across the recent literature, PICK1’s primary molecular role is best
            described as a **PDZ/BAR scaffold that regulates the trafficking and surface
            availability of membrane proteins—especially AMPA-type glutamate receptors—by
            coordinating protein complex assembly with membrane remodeling and endocytic/recycling
            processes**
        - reference_id: file:human/PICK1/PICK1-deep-research-falcon.md
          supporting_text: Human **PICK1 (Q9NRD5)** is best annotated as a **PDZ/BAR scaffolding and
            membrane-remodeling protein** that controls **membrane protein trafficking**, with the
            strongest 2023–2024 evidence supporting roles in **AMPAR (GluA2/3)
            internalization/recycling and synaptic plasticity** through phosphorylation-dependent
            partner switching and regulated complex formation.
  - term:
      id: GO:0045161
      label: neuronal ion channel clustering
    evidence_type: TAS
    original_reference_id: PMID:11343649
    review:
      summary: Neuronal ion channel clustering is consistent with PICK1 synaptic receptor clustering
        and trafficking roles.
      action: ACCEPT
      reason: neuronal ion channel clustering is supported as part of PICK1 PDZ/BAR scaffold,
        membrane-remodeling, or synaptic receptor-trafficking function.
      supported_by:
        - reference_id: file:human/PICK1/PICK1-deep-research-falcon.md
          supporting_text: Across the recent literature, PICK1’s primary molecular role is best
            described as a **PDZ/BAR scaffold that regulates the trafficking and surface
            availability of membrane proteins—especially AMPA-type glutamate receptors—by
            coordinating protein complex assembly with membrane remodeling and endocytic/recycling
            processes**
        - reference_id: file:human/PICK1/PICK1-deep-research-falcon.md
          supporting_text: PICK1 is described as enriched in brain and localized to **pre- and
            postsynaptic compartments**, consistent with its role in regulating synaptic receptor
            trafficking
references:
  - id: GO_REF:0000002
    title: Gene Ontology annotation through association of InterPro records with GO terms
    findings: []
  - id: GO_REF:0000024
    title: Manual transfer of experimentally-verified manual GO annotation data to orthologs by
      curator judgment of sequence similarity
    findings: []
  - id: GO_REF:0000033
    title: Annotation inferences using phylogenetic trees
    findings: []
  - id: GO_REF:0000043
    title: Gene Ontology annotation based on UniProtKB/Swiss-Prot keyword mapping
    findings: []
  - id: GO_REF:0000044
    title: Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location vocabulary
      mapping, accompanied by conservative changes to GO terms applied by UniProt
    findings: []
  - id: GO_REF:0000052
    title: Gene Ontology annotation based on curation of immunofluorescence data
    findings: []
  - id: GO_REF:0000117
    title: Electronic Gene Ontology annotations created by ARBA machine learning models
    findings: []
  - id: GO_REF:0000120
    title: Combined Automated Annotation using Multiple IEA Methods
    findings: []
  - id: PMID:11343649
    title: Functional interaction between monoamine plasma membrane transporters and the synaptic
      PDZ domain-containing protein PICK1.
    findings: []
  - id: PMID:11802773
    title: Interaction of the synaptic protein PICK1 (protein interacting with C kinase 1) with the
      non-voltage gated sodium channels BNC1 (brain Na+ channel 1) and ASIC (acid-sensing ion
      channel).
    findings: []
  - id: PMID:16314870
    title: 'Serine racemase binds to PICK1: potential relevance to schizophrenia.'
    findings: []
  - id: PMID:16713569
    title: A protein-protein interaction network for human inherited ataxias and disorders of
      Purkinje cell degeneration.
    findings: []
  - id: PMID:21653829
    title: Protein interactome reveals converging molecular pathways among autism disorders.
    findings: []
  - id: PMID:26787460
    title: Proteomic peptide phage display uncovers novel interactions of the PDZ1-2 supramodule of
      syntenin.
    findings: []
  - id: PMID:28514442
    title: Architecture of the human interactome defines protein communities and disease networks.
    findings: []
  - id: PMID:29768204
    title: An Amphipathic Helix Directs Cellular Membrane Curvature Sensing and Function of the BAR
      Domain Protein PICK1.
    findings: []
  - id: PMID:31413325
    title: HENA, heterogeneous network-based data set for Alzheimer's disease.
    findings: []
  - id: PMID:32296183
    title: A reference map of the human binary protein interactome.
    findings: []
  - id: PMID:32814053
    title: Interactome Mapping Provides a Network of Neurodegenerative Disease Proteins and Uncovers
      Widespread Protein Aggregation in Affected Brains.
    findings: []
  - id: PMID:33961781
    title: Dual proteome-scale networks reveal cell-specific remodeling of the human interactome.
    findings: []
  - id: PMID:36115835
    title: Quantitative fragmentomics allow affinity mapping of interactomes.
    findings: []
  - id: PMID:37207277
    title: Using brain cell-type-specific protein interactomes to interpret neurodevelopmental
      genetic signals in schizophrenia.
    findings: []
  - id: Reactome:R-HSA-416639
    title: Trafficking of GluR2-containing AMPA receptors to extrasynaptic sites
    findings: []
  - id: Reactome:R-HSA-416985
    title: Trafficking of GluR2-containing AMPA receptors to synapse
    findings: []
  - id: Reactome:R-HSA-421007
    title: Endocytosis of Ca impermeable AMPA receptors
    findings: []
  - id: file:human/PICK1/PICK1-deep-research-falcon.md
    title: Falcon deep research synthesis for PICK1
    findings: []
core_functions:
  - description: PDZ-domain scaffold activity that selects receptor/cargo partners such as AMPAR
      GluA2/GluA3 and regulates receptor internalization, clustering, and synaptic trafficking.
    molecular_function:
      id: GO:0019904
      label: protein domain specific binding
    directly_involved_in:
      - id: GO:0002092
        label: positive regulation of receptor internalization
      - id: GO:0043113
        label: receptor clustering
      - id: GO:0006886
        label: intracellular protein transport
      - id: GO:0060292
        label: long-term synaptic depression
    locations:
      - id: GO:0014069
        label: postsynaptic density
      - id: GO:0045202
        label: synapse
      - id: GO:0005886
        label: plasma membrane
    supported_by:
      - reference_id: file:human/PICK1/PICK1-deep-research-falcon.md
        supporting_text: '**PDZ domain (protein interaction module):** In AMPAR biology, authoritative
          review evidence states that the **GluA2 C-terminus** contains a PDZ ligand that binds directly
          to **PICK1** (and GRIP1), and that PICK1 binds GluA2 via its PDZ domain'
      - reference_id: file:human/PICK1/PICK1-deep-research-falcon.md
        supporting_text: In vivo evidence from mouse hippocampus (kainic acid model) supports a
          mechanistic switch in which **GluA2 Ser880 phosphorylation** promotes dissociation from
          GRIP1 and association with PICK1, driving AMPAR endocytosis/internalization; PP2A-mediated
          dephosphorylation reverses this and disfavors PICK1 association
      - reference_id: file:human/PICK1/PICK1-deep-research-falcon.md
        supporting_text: Human **PICK1 (Q9NRD5)** is best annotated as a **PDZ/BAR scaffolding and
          membrane-remodeling protein** that controls **membrane protein trafficking**, with the
          strongest 2023–2024 evidence supporting roles in **AMPAR (GluA2/3)
          internalization/recycling and synaptic plasticity** through phosphorylation-dependent
          partner switching and regulated complex formation.
  - description: BAR/N-BAR membrane binding and curvature-sensing activity that couples PICK1 cargo
      complexes to membrane remodeling and compartmentalized trafficking.
    molecular_function:
      id: GO:0140090
      label: membrane curvature sensor activity
    directly_involved_in:
      - id: GO:0006886
        label: intracellular protein transport
      - id: GO:0002092
        label: positive regulation of receptor internalization
    locations:
      - id: GO:0030666
        label: endocytic vesicle membrane
    supported_by:
      - reference_id: file:human/PICK1/PICK1-deep-research-falcon.md
        supporting_text: '**PICK1 is a dual-domain scaffolding/adaptor protein** that couples (i) **PDZ-domain–mediated
          binding** to C-terminal motifs on cargo proteins with (ii) **BAR/N‑BAR–mediated lipid/membrane
          binding and remodeling**, enabling regulation of membrane protein trafficking and compartmentalization'
      - reference_id: file:human/PICK1/PICK1-deep-research-falcon.md
        supporting_text: '**BAR / N‑BAR domain (membrane remodeling module):** BAR domains are classically
          crescent-shaped, lipid-binding modules involved in membrane curvature during trafficking.'
      - reference_id: file:human/PICK1/PICK1-deep-research-falcon.md
        supporting_text: Across the recent literature, PICK1’s primary molecular role is best
          described as a **PDZ/BAR scaffold that regulates the trafficking and surface availability
          of membrane proteins—especially AMPA-type glutamate receptors—by coordinating protein
          complex assembly with membrane remodeling and endocytic/recycling processes**
proposed_new_terms: []
suggested_questions: []
suggested_experiments: []

Gene Description

Existing Annotations Review

Core Functions

PDZ-domain scaffold activity that selects receptor/cargo partners such as AMPAR GluA2/GluA3 and regulates receptor internalization, clustering, and synaptic trafficking.

BAR/N-BAR membrane binding and curvature-sensing activity that couples PICK1 cargo complexes to membrane remodeling and compartmentalized trafficking.

References

Deep Research

Falcon

Research Report: Human PICK1 (UniProt Q9NRD5) — Functional Annotation and Recent Research (2023–2024)

0. Target verification (mandatory)

1. Key concepts and definitions (current understanding)

1.1. What PICK1 is

1.2. Core domains and what they imply functionally

1.3. Primary molecular function (functional annotation statement)

2. Biological processes, pathways, and binding partners

2.1. AMPA receptor (AMPAR) trafficking and synaptic plasticity (central pathway)

2.2. PKCα (PRKCA) linkage

2.3. CaMKII linkage

3. Subcellular localization (where PICK1 acts)

3.1. Neuronal compartments: pre-/postsynaptic regions

3.2. ER membrane trafficking context

3.3. Cytosol/perinuclear localization and stress-induced aggresome recruitment

4. Recent developments and latest research (prioritizing 2023–2024)

4.1. 2024 translational advance: PDZ-domain targeting for obesity treatment (real-world implementation trend)

4.2. 2024 mechanistic advance: arsenite stress, BAR-domain homodimerization, and aggresomes

4.3. 2023 mechanistic evidence: PP2A–GluA2 S880–PICK1 axis in vivo

4.4. 2023–2024 receptor-signaling linkage: M1 mAChR → PICK1 → GluA2 trafficking

4.5. 2023 structural/biophysical developments: BAR-domain mechanics

5. Current applications and real-world implementations

5.1. Therapeutic targeting of PICK1 PDZ interactions

5.2. Cancer biology and biomarker potential

6. Expert opinions and authoritative synthesis (with analysis)

6.1. Consensus model

6.2. Reconciling apparent “pleiotropy”

7. Relevant statistics and data points (from recent studies)

8. Disease associations (database-level context)

9. Summary (functional annotation statement)

Citations

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