PICALM

UniProt ID: Q13492
Organism: Homo sapiens
Review Status: COMPLETE
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Gene Description

PICALM encodes CALM, a ubiquitously expressed ANTH-domain clathrin adaptor that binds phosphatidylinositol phosphates, clathrin, AP-2, and selected cargo proteins to promote clathrin-coated pit maturation and clathrin-mediated endocytosis. It localizes mainly to cytosolic membrane interfaces including plasma membrane clathrin-coated pits, clathrin-coated vesicles, Golgi/endosomal compartments, and synaptic vesicle-related membranes. PICALM helps determine clathrin-coated vesicle size and membrane curvature, and it sorts small R-SNAREs such as VAMP2, VAMP3, and VAMP8 between the plasma membrane and endosomes. Cargo- and tissue-specific consequences include transferrin receptor/iron uptake, AMPA receptor trafficking, gamma-secretase and APP-related trafficking, amyloid-beta transcytosis across brain endothelium, and association with tau pathology.

Existing Annotations Review

GO Term Evidence Action Reason
GO:0072583 clathrin-dependent endocytosis
IBA
GO_REF:0000033 		ACCEPT
Summary: This endocytosis/receptor-internalization term captures the core PICALM role in clathrin-mediated internalization and coated-vesicle maturation.
Reason: This term aligns with the core PICALM/CALM role as a phosphoinositide-binding clathrin adaptor that organizes clathrin-coated pits/vesicles, controls vesicle curvature and maturation, and sorts endocytic cargo including small R-SNAREs.
GO:0005546 phosphatidylinositol-4,5-bisphosphate binding
IBA
GO_REF:0000033 		ACCEPT
Summary: PICALM/CALM uses its ANTH domain to bind phosphoinositides/PIP2 at clathrin-coated membrane sites, anchoring its endocytic adaptor and curvature functions.
Reason: This term aligns with the core PICALM/CALM role as a phosphoinositide-binding clathrin adaptor that organizes clathrin-coated pits/vesicles, controls vesicle curvature and maturation, and sorts endocytic cargo including small R-SNAREs.
GO:0006900 vesicle budding from membrane
IBA
GO_REF:0000033 		ACCEPT
Summary: This vesicle/coated-pit term is consistent with PICALM acting at clathrin-coated pits and clathrin-coated vesicle intermediates.
Reason: This term aligns with the core PICALM/CALM role as a phosphoinositide-binding clathrin adaptor that organizes clathrin-coated pits/vesicles, controls vesicle curvature and maturation, and sorts endocytic cargo including small R-SNAREs.
GO:0098894 extrinsic component of presynaptic endocytic zone membrane
IBA
GO_REF:0000033 		ACCEPT
Summary: This localization/process is consistent with PICALM acting at cytosolic membrane interfaces for clathrin-mediated endocytosis and vesicle trafficking.
Reason: This location is consistent with PICALM/CALM recruitment to cytosolic membrane interfaces used for clathrin-mediated endocytosis, clathrin-coated vesicle formation, SNARE sorting, and endosomal/synaptic vesicle trafficking.
GO:0005905 clathrin-coated pit
IBA
GO_REF:0000033 		ACCEPT
Summary: This vesicle/coated-pit term is consistent with PICALM acting at clathrin-coated pits and clathrin-coated vesicle intermediates.
Reason: This location is consistent with PICALM/CALM recruitment to cytosolic membrane interfaces used for clathrin-mediated endocytosis, clathrin-coated vesicle formation, SNARE sorting, and endosomal/synaptic vesicle trafficking.
GO:0000149 SNARE binding
IBA
GO_REF:0000033 		ACCEPT
Summary: PICALM directly binds small R-SNAREs such as VAMP2, VAMP3, and VAMP8 and mediates their endocytosis.
Reason: This term aligns with the core PICALM/CALM role as a phosphoinositide-binding clathrin adaptor that organizes clathrin-coated pits/vesicles, controls vesicle curvature and maturation, and sorts endocytic cargo including small R-SNAREs.
GO:0030136 clathrin-coated vesicle
IBA
GO_REF:0000033 		ACCEPT
Summary: This vesicle/coated-pit term is consistent with PICALM acting at clathrin-coated pits and clathrin-coated vesicle intermediates.
Reason: This location is consistent with PICALM/CALM recruitment to cytosolic membrane interfaces used for clathrin-mediated endocytosis, clathrin-coated vesicle formation, SNARE sorting, and endosomal/synaptic vesicle trafficking.
GO:0005545 1-phosphatidylinositol binding
IBA
GO_REF:0000033 		ACCEPT
Summary: PICALM/CALM uses its ANTH domain to bind phosphoinositides/PIP2 at clathrin-coated membrane sites, anchoring its endocytic adaptor and curvature functions.
Reason: This term aligns with the core PICALM/CALM role as a phosphoinositide-binding clathrin adaptor that organizes clathrin-coated pits/vesicles, controls vesicle curvature and maturation, and sorts endocytic cargo including small R-SNAREs.
GO:0008021 synaptic vesicle
IBA
GO_REF:0000033 		ACCEPT
Summary: This synaptic-vesicle/presynaptic term is consistent with PICALM/AP180-family SNARE sorting and synaptic vesicle trafficking biology.
Reason: This location is consistent with PICALM/CALM recruitment to cytosolic membrane interfaces used for clathrin-mediated endocytosis, clathrin-coated vesicle formation, SNARE sorting, and endosomal/synaptic vesicle trafficking.
GO:0032050 clathrin heavy chain binding
IBA
GO_REF:0000033 		ACCEPT
Summary: Direct clathrin/clathrin-heavy-chain binding is central to PICALM recruitment and clathrin-coated pit/vesicle assembly.
Reason: This term aligns with the core PICALM/CALM role as a phosphoinositide-binding clathrin adaptor that organizes clathrin-coated pits/vesicles, controls vesicle curvature and maturation, and sorts endocytic cargo including small R-SNAREs.
GO:0005543 phospholipid binding
IEA
GO_REF:0000002 		ACCEPT
Summary: PICALM/CALM uses its ANTH domain to bind phosphoinositides/PIP2 at clathrin-coated membrane sites, anchoring its endocytic adaptor and curvature functions.
Reason: This term aligns with the core PICALM/CALM role as a phosphoinositide-binding clathrin adaptor that organizes clathrin-coated pits/vesicles, controls vesicle curvature and maturation, and sorts endocytic cargo including small R-SNAREs.
GO:0005545 1-phosphatidylinositol binding
IEA
GO_REF:0000002 		ACCEPT
Summary: PICALM/CALM uses its ANTH domain to bind phosphoinositides/PIP2 at clathrin-coated membrane sites, anchoring its endocytic adaptor and curvature functions.
Reason: This term aligns with the core PICALM/CALM role as a phosphoinositide-binding clathrin adaptor that organizes clathrin-coated pits/vesicles, controls vesicle curvature and maturation, and sorts endocytic cargo including small R-SNAREs.
GO:0005634 nucleus
IEA
GO_REF:0000044 		KEEP AS NON CORE
Summary: Nuclear localization and transcriptional effects are context-specific, mainly from nuclear shuttling or leukemia-fusion/interactor biology, and are not the principal PICALM function.
Reason: Retain as non-core because the annotation is supported or plausible but represents a cargo-specific, disease-model, endothelial, iron-homeostasis, nuclear/leukemia, or downstream phenotype rather than the primary clathrin/SNARE adaptor function.
GO:0005794 Golgi apparatus
IEA
GO_REF:0000044 		ACCEPT
Summary: This localization/process is consistent with PICALM acting at cytosolic membrane interfaces for clathrin-mediated endocytosis and vesicle trafficking.
Reason: This location is consistent with PICALM/CALM recruitment to cytosolic membrane interfaces used for clathrin-mediated endocytosis, clathrin-coated vesicle formation, SNARE sorting, and endosomal/synaptic vesicle trafficking.
GO:0005886 plasma membrane
IEA
GO_REF:0000044 		ACCEPT
Summary: This localization/process is consistent with PICALM acting at cytosolic membrane interfaces for clathrin-mediated endocytosis and vesicle trafficking.
Reason: This location is consistent with PICALM/CALM recruitment to cytosolic membrane interfaces used for clathrin-mediated endocytosis, clathrin-coated vesicle formation, SNARE sorting, and endosomal/synaptic vesicle trafficking.
GO:0005905 clathrin-coated pit
IEA
GO_REF:0000044 		ACCEPT
Summary: This vesicle/coated-pit term is consistent with PICALM acting at clathrin-coated pits and clathrin-coated vesicle intermediates.
Reason: This location is consistent with PICALM/CALM recruitment to cytosolic membrane interfaces used for clathrin-mediated endocytosis, clathrin-coated vesicle formation, SNARE sorting, and endosomal/synaptic vesicle trafficking.
GO:0006897 endocytosis
IEA
GO_REF:0000117 		ACCEPT
Summary: This endocytosis/receptor-internalization term captures the core PICALM role in clathrin-mediated internalization and coated-vesicle maturation.
Reason: This term aligns with the core PICALM/CALM role as a phosphoinositide-binding clathrin adaptor that organizes clathrin-coated pits/vesicles, controls vesicle curvature and maturation, and sorts endocytic cargo including small R-SNAREs.
GO:0012505 endomembrane system
IEA
GO_REF:0000117 		ACCEPT
Summary: This localization/process is consistent with PICALM acting at cytosolic membrane interfaces for clathrin-mediated endocytosis and vesicle trafficking.
Reason: This location is consistent with PICALM/CALM recruitment to cytosolic membrane interfaces used for clathrin-mediated endocytosis, clathrin-coated vesicle formation, SNARE sorting, and endosomal/synaptic vesicle trafficking.
GO:0016020 membrane
IEA
GO_REF:0000117 		ACCEPT
Summary: This localization/process is consistent with PICALM acting at cytosolic membrane interfaces for clathrin-mediated endocytosis and vesicle trafficking.
Reason: This location is consistent with PICALM/CALM recruitment to cytosolic membrane interfaces used for clathrin-mediated endocytosis, clathrin-coated vesicle formation, SNARE sorting, and endosomal/synaptic vesicle trafficking.
GO:0030136 clathrin-coated vesicle
IEA
GO_REF:0000120 		ACCEPT
Summary: This vesicle/coated-pit term is consistent with PICALM acting at clathrin-coated pits and clathrin-coated vesicle intermediates.
Reason: This location is consistent with PICALM/CALM recruitment to cytosolic membrane interfaces used for clathrin-mediated endocytosis, clathrin-coated vesicle formation, SNARE sorting, and endosomal/synaptic vesicle trafficking.
GO:0030276 clathrin binding
IEA
GO_REF:0000002 		ACCEPT
Summary: Direct clathrin/clathrin-heavy-chain binding is central to PICALM recruitment and clathrin-coated pit/vesicle assembly.
Reason: This term aligns with the core PICALM/CALM role as a phosphoinositide-binding clathrin adaptor that organizes clathrin-coated pits/vesicles, controls vesicle curvature and maturation, and sorts endocytic cargo including small R-SNAREs.
GO:0031982 vesicle
IEA
GO_REF:0000117 		ACCEPT
Summary: This vesicle/coated-pit term is consistent with PICALM acting at clathrin-coated pits and clathrin-coated vesicle intermediates.
Reason: This location is consistent with PICALM/CALM recruitment to cytosolic membrane interfaces used for clathrin-mediated endocytosis, clathrin-coated vesicle formation, SNARE sorting, and endosomal/synaptic vesicle trafficking.
GO:0048259 regulation of receptor-mediated endocytosis
IEA
GO_REF:0000117 		ACCEPT
Summary: This endocytosis/receptor-internalization term captures the core PICALM role in clathrin-mediated internalization and coated-vesicle maturation.
Reason: This term aligns with the core PICALM/CALM role as a phosphoinositide-binding clathrin adaptor that organizes clathrin-coated pits/vesicles, controls vesicle curvature and maturation, and sorts endocytic cargo including small R-SNAREs.
GO:0048268 clathrin coat assembly
IEA
GO_REF:0000002 		ACCEPT
Summary: PICALM is required for orderly clathrin coat and coated-bud formation at the plasma membrane.
Reason: This term aligns with the core PICALM/CALM role as a phosphoinositide-binding clathrin adaptor that organizes clathrin-coated pits/vesicles, controls vesicle curvature and maturation, and sorts endocytic cargo including small R-SNAREs.
GO:0072583 clathrin-dependent endocytosis
IEA
GO_REF:0000002 		ACCEPT
Summary: This endocytosis/receptor-internalization term captures the core PICALM role in clathrin-mediated internalization and coated-vesicle maturation.
Reason: This term aligns with the core PICALM/CALM role as a phosphoinositide-binding clathrin adaptor that organizes clathrin-coated pits/vesicles, controls vesicle curvature and maturation, and sorts endocytic cargo including small R-SNAREs.
GO:0005515 protein binding
IPI
PMID:22829078
FHL2 interacts with CALM and is highly expressed in acute er... 		MARK AS OVER ANNOTATED
Summary: The interaction evidence may be real, but generic protein binding is not informative for PICALM because specific clathrin, clathrin heavy chain, SNARE, phosphoinositide, and cargo-adaptor annotations are available.
Reason: This is less informative or less direct than the specific PICALM functions supported by the evidence; prefer clathrin, clathrin heavy chain, SNARE, phosphoinositide, and cargo-trafficking annotations where applicable.
GO:0005515 protein binding
IPI
PMID:26496610
A human interactome in three quantitative dimensions organiz... 		MARK AS OVER ANNOTATED
Summary: The interaction evidence may be real, but generic protein binding is not informative for PICALM because specific clathrin, clathrin heavy chain, SNARE, phosphoinositide, and cargo-adaptor annotations are available.
Reason: This is less informative or less direct than the specific PICALM functions supported by the evidence; prefer clathrin, clathrin heavy chain, SNARE, phosphoinositide, and cargo-trafficking annotations where applicable.
GO:0005515 protein binding
IPI
PMID:35044719
Proteome-scale mapping of binding sites in the unstructured ... 		MARK AS OVER ANNOTATED
Summary: The interaction evidence may be real, but generic protein binding is not informative for PICALM because specific clathrin, clathrin heavy chain, SNARE, phosphoinositide, and cargo-adaptor annotations are available.
Reason: This is less informative or less direct than the specific PICALM functions supported by the evidence; prefer clathrin, clathrin heavy chain, SNARE, phosphoinositide, and cargo-trafficking annotations where applicable.
GO:0005794 Golgi apparatus
EXP
PMID:10436022
Clathrin assembly lymphoid myeloid leukemia (CALM) protein: ... 		ACCEPT
Summary: This localization/process is consistent with PICALM acting at cytosolic membrane interfaces for clathrin-mediated endocytosis and vesicle trafficking.
Reason: This location is consistent with PICALM/CALM recruitment to cytosolic membrane interfaces used for clathrin-mediated endocytosis, clathrin-coated vesicle formation, SNARE sorting, and endosomal/synaptic vesicle trafficking.
GO:0046579 positive regulation of Ras protein signal transduction
IMP
PMID:26005850
Central role for PICALM in amyloid-β blood-brain barrier tra... 		KEEP AS NON CORE
Summary: This annotation is supported or plausible for a specific cellular or disease context, but it is not the primary PICALM clathrin/SNARE adaptor function.
Reason: Retain as non-core because the annotation is supported or plausible but represents a cargo-specific, disease-model, endothelial, iron-homeostasis, nuclear/leukemia, or downstream phenotype rather than the primary clathrin/SNARE adaptor function.
GO:1902991 regulation of amyloid precursor protein catabolic process
IMP
PMID:24577224
Decreased CALM expression reduces Aβ42 to total Aβ ratio thr... 		KEEP AS NON CORE
Summary: The gamma-secretase/APP processing annotation is supported as a cargo-specific consequence of CALM-dependent clathrin-mediated endocytosis, not as a separate catalytic activity.
Reason: Retain as non-core because the annotation is supported or plausible but represents a cargo-specific, disease-model, endothelial, iron-homeostasis, nuclear/leukemia, or downstream phenotype rather than the primary clathrin/SNARE adaptor function.
GO:1902993 positive regulation of amyloid precursor protein catabolic process
ISS
GO_REF:0000024 		KEEP AS NON CORE
Summary: This annotation is supported or plausible for a specific cellular or disease context, but it is not the primary PICALM clathrin/SNARE adaptor function.
Reason: Retain as non-core because the annotation is supported or plausible but represents a cargo-specific, disease-model, endothelial, iron-homeostasis, nuclear/leukemia, or downstream phenotype rather than the primary clathrin/SNARE adaptor function.
GO:0048268 clathrin coat assembly
IDA
PMID:16262731
Effect of clathrin assembly lymphoid myeloid leukemia protei... 		ACCEPT
Summary: PICALM is required for orderly clathrin coat and coated-bud formation at the plasma membrane.
Reason: This term aligns with the core PICALM/CALM role as a phosphoinositide-binding clathrin adaptor that organizes clathrin-coated pits/vesicles, controls vesicle curvature and maturation, and sorts endocytic cargo including small R-SNAREs.
GO:0006879 intracellular iron ion homeostasis
IMP
PMID:22952941
The PICALM protein plays a key role in iron homeostasis and ... 		KEEP AS NON CORE
Summary: The iron-homeostasis and linked expression/proliferation phenotypes are supported, but they arise downstream of transferrin receptor endocytosis rather than defining the primary molecular role.
Reason: Retain as non-core because the annotation is supported or plausible but represents a cargo-specific, disease-model, endothelial, iron-homeostasis, nuclear/leukemia, or downstream phenotype rather than the primary clathrin/SNARE adaptor function.
GO:0060586 multicellular organismal-level iron ion homeostasis
IMP
PMID:22952941
The PICALM protein plays a key role in iron homeostasis and ... 		KEEP AS NON CORE
Summary: The iron-homeostasis and linked expression/proliferation phenotypes are supported, but they arise downstream of transferrin receptor endocytosis rather than defining the primary molecular role.
Reason: Retain as non-core because the annotation is supported or plausible but represents a cargo-specific, disease-model, endothelial, iron-homeostasis, nuclear/leukemia, or downstream phenotype rather than the primary clathrin/SNARE adaptor function.
GO:0150093 amyloid-beta clearance by transcytosis
ISS
PMID:26005850
Central role for PICALM in amyloid-β blood-brain barrier tra... 		KEEP AS NON CORE
Summary: The BBB/endothelial amyloid-beta clearance evidence is strong and Alzheimer-relevant, but it is a cargo- and tissue-specific consequence of PICALM-mediated endocytic/transcytotic trafficking.
Reason: Retain as non-core because the annotation is supported or plausible but represents a cargo-specific, disease-model, endothelial, iron-homeostasis, nuclear/leukemia, or downstream phenotype rather than the primary clathrin/SNARE adaptor function.
GO:0030132 clathrin coat of coated pit
IDA
PMID:10436022
Clathrin assembly lymphoid myeloid leukemia (CALM) protein: ... 		ACCEPT
Summary: PICALM is required for orderly clathrin coat and coated-bud formation at the plasma membrane.
Reason: This location is consistent with PICALM/CALM recruitment to cytosolic membrane interfaces used for clathrin-mediated endocytosis, clathrin-coated vesicle formation, SNARE sorting, and endosomal/synaptic vesicle trafficking.
GO:0030132 clathrin coat of coated pit
IDA
PMID:16262731
Effect of clathrin assembly lymphoid myeloid leukemia protei... 		ACCEPT
Summary: PICALM is required for orderly clathrin coat and coated-bud formation at the plasma membrane.
Reason: This location is consistent with PICALM/CALM recruitment to cytosolic membrane interfaces used for clathrin-mediated endocytosis, clathrin-coated vesicle formation, SNARE sorting, and endosomal/synaptic vesicle trafficking.
GO:0031267 small GTPase binding
IPI
PMID:26005850
Central role for PICALM in amyloid-β blood-brain barrier tra... 		KEEP AS NON CORE
Summary: The BBB/endothelial amyloid-beta clearance evidence is strong and Alzheimer-relevant, but it is a cargo- and tissue-specific consequence of PICALM-mediated endocytic/transcytotic trafficking.
Reason: Retain as non-core because the annotation is supported or plausible but represents a cargo-specific, disease-model, endothelial, iron-homeostasis, nuclear/leukemia, or downstream phenotype rather than the primary clathrin/SNARE adaptor function.
GO:0050750 low-density lipoprotein particle receptor binding
IPI
PMID:26005850
Central role for PICALM in amyloid-β blood-brain barrier tra... 		KEEP AS NON CORE
Summary: The BBB/endothelial amyloid-beta clearance evidence is strong and Alzheimer-relevant, but it is a cargo- and tissue-specific consequence of PICALM-mediated endocytic/transcytotic trafficking.
Reason: Retain as non-core because the annotation is supported or plausible but represents a cargo-specific, disease-model, endothelial, iron-homeostasis, nuclear/leukemia, or downstream phenotype rather than the primary clathrin/SNARE adaptor function.
GO:0000149 SNARE binding
IDA
PMID:22118466
The molecular basis for the endocytosis of small R-SNAREs by... 		ACCEPT
Summary: PICALM directly binds small R-SNAREs such as VAMP2, VAMP3, and VAMP8 and mediates their endocytosis.
Reason: This term aligns with the core PICALM/CALM role as a phosphoinositide-binding clathrin adaptor that organizes clathrin-coated pits/vesicles, controls vesicle curvature and maturation, and sorts endocytic cargo including small R-SNAREs.
GO:0005515 protein binding
IPI
PMID:22118466
The molecular basis for the endocytosis of small R-SNAREs by... 		MARK AS OVER ANNOTATED
Summary: The interaction evidence may be real, but generic protein binding is not informative for PICALM because specific clathrin, clathrin heavy chain, SNARE, phosphoinositide, and cargo-adaptor annotations are available.
Reason: This is less informative or less direct than the specific PICALM functions supported by the evidence; prefer clathrin, clathrin heavy chain, SNARE, phosphoinositide, and cargo-trafficking annotations where applicable.
GO:0006897 endocytosis
IDA
PMID:22118466
The molecular basis for the endocytosis of small R-SNAREs by... 		ACCEPT
Summary: This endocytosis/receptor-internalization term captures the core PICALM role in clathrin-mediated internalization and coated-vesicle maturation.
Reason: This term aligns with the core PICALM/CALM role as a phosphoinositide-binding clathrin adaptor that organizes clathrin-coated pits/vesicles, controls vesicle curvature and maturation, and sorts endocytic cargo including small R-SNAREs.
GO:0005515 protein binding
IPI
PMID:16262731
Effect of clathrin assembly lymphoid myeloid leukemia protei... 		MARK AS OVER ANNOTATED
Summary: The interaction evidence may be real, but generic protein binding is not informative for PICALM because specific clathrin, clathrin heavy chain, SNARE, phosphoinositide, and cargo-adaptor annotations are available.
Reason: This is less informative or less direct than the specific PICALM functions supported by the evidence; prefer clathrin, clathrin heavy chain, SNARE, phosphoinositide, and cargo-trafficking annotations where applicable.
GO:0005886 plasma membrane
IDA
PMID:16262731
Effect of clathrin assembly lymphoid myeloid leukemia protei... 		ACCEPT
Summary: This localization/process is consistent with PICALM acting at cytosolic membrane interfaces for clathrin-mediated endocytosis and vesicle trafficking.
Reason: This location is consistent with PICALM/CALM recruitment to cytosolic membrane interfaces used for clathrin-mediated endocytosis, clathrin-coated vesicle formation, SNARE sorting, and endosomal/synaptic vesicle trafficking.
GO:0072583 clathrin-dependent endocytosis
IMP
PMID:26005850
Central role for PICALM in amyloid-β blood-brain barrier tra... 		ACCEPT
Summary: This endocytosis/receptor-internalization term captures the core PICALM role in clathrin-mediated internalization and coated-vesicle maturation.
Reason: This term aligns with the core PICALM/CALM role as a phosphoinositide-binding clathrin adaptor that organizes clathrin-coated pits/vesicles, controls vesicle curvature and maturation, and sorts endocytic cargo including small R-SNAREs.
GO:0150093 amyloid-beta clearance by transcytosis
IGI
PMID:26005850
Central role for PICALM in amyloid-β blood-brain barrier tra... 		KEEP AS NON CORE
Summary: The BBB/endothelial amyloid-beta clearance evidence is strong and Alzheimer-relevant, but it is a cargo- and tissue-specific consequence of PICALM-mediated endocytic/transcytotic trafficking.
Reason: Retain as non-core because the annotation is supported or plausible but represents a cargo-specific, disease-model, endothelial, iron-homeostasis, nuclear/leukemia, or downstream phenotype rather than the primary clathrin/SNARE adaptor function.
GO:0001540 amyloid-beta binding
IC
GO_REF:0000111 		MARK AS OVER ANNOTATED
Summary: Amyloid-beta binding is not directly established for PICALM in the cited inference; the cached BBB study supports PICALM-dependent A-beta/LRP1 trafficking and direct LRP1-tail binding rather than direct amyloid-beta binding.
Reason: This is less informative or less direct than the specific PICALM functions supported by the evidence; prefer clathrin, clathrin heavy chain, SNARE, phosphoinositide, and cargo-trafficking annotations where applicable.
GO:0006900 vesicle budding from membrane
IMP
PMID:25898166
CALM regulates clathrin-coated vesicle size and maturation b... 		ACCEPT
Summary: This vesicle/coated-pit term is consistent with PICALM acting at clathrin-coated pits and clathrin-coated vesicle intermediates.
Reason: This term aligns with the core PICALM/CALM role as a phosphoinositide-binding clathrin adaptor that organizes clathrin-coated pits/vesicles, controls vesicle curvature and maturation, and sorts endocytic cargo including small R-SNAREs.
GO:0048156 tau protein binding
IPI
PMID:23589030
Clathrin adaptor CALM/PICALM is associated with neurofibrill... 		KEEP AS NON CORE
Summary: The tau/neurofibrillary-tangle evidence is Alzheimer-relevant, but it reflects pathology-associated localization or binding rather than the main clathrin/SNARE adaptor role.
Reason: Retain as non-core because the annotation is supported or plausible but represents a cargo-specific, disease-model, endothelial, iron-homeostasis, nuclear/leukemia, or downstream phenotype rather than the primary clathrin/SNARE adaptor function.
GO:0045296 cadherin binding
HDA
PMID:25468996
E-cadherin interactome complexity and robustness resolved by... 		MARK AS OVER ANNOTATED
Summary: The high-throughput cadherin-binding annotation is peripheral to PICALM endocytic adaptor biology and is less informative than the supported clathrin/SNARE/phosphoinositide binding terms.
Reason: This is less informative or less direct than the specific PICALM functions supported by the evidence; prefer clathrin, clathrin heavy chain, SNARE, phosphoinositide, and cargo-trafficking annotations where applicable.
GO:0031623 receptor internalization
IMP
PMID:25898166
CALM regulates clathrin-coated vesicle size and maturation b... 		ACCEPT
Summary: This endocytosis/receptor-internalization term captures the core PICALM role in clathrin-mediated internalization and coated-vesicle maturation.
Reason: This term aligns with the core PICALM/CALM role as a phosphoinositide-binding clathrin adaptor that organizes clathrin-coated pits/vesicles, controls vesicle curvature and maturation, and sorts endocytic cargo including small R-SNAREs.
GO:0005546 phosphatidylinositol-4,5-bisphosphate binding
ISS
PMID:25898166
CALM regulates clathrin-coated vesicle size and maturation b... 		ACCEPT
Summary: PICALM/CALM uses its ANTH domain to bind phosphoinositides/PIP2 at clathrin-coated membrane sites, anchoring its endocytic adaptor and curvature functions.
Reason: This term aligns with the core PICALM/CALM role as a phosphoinositide-binding clathrin adaptor that organizes clathrin-coated pits/vesicles, controls vesicle curvature and maturation, and sorts endocytic cargo including small R-SNAREs.
GO:0005905 clathrin-coated pit
IMP
PMID:25898166
CALM regulates clathrin-coated vesicle size and maturation b... 		ACCEPT
Summary: This vesicle/coated-pit term is consistent with PICALM acting at clathrin-coated pits and clathrin-coated vesicle intermediates.
Reason: This location is consistent with PICALM/CALM recruitment to cytosolic membrane interfaces used for clathrin-mediated endocytosis, clathrin-coated vesicle formation, SNARE sorting, and endosomal/synaptic vesicle trafficking.
GO:0016020 membrane
ISS
PMID:25898166
CALM regulates clathrin-coated vesicle size and maturation b... 		ACCEPT
Summary: This localization/process is consistent with PICALM acting at cytosolic membrane interfaces for clathrin-mediated endocytosis and vesicle trafficking.
Reason: This location is consistent with PICALM/CALM recruitment to cytosolic membrane interfaces used for clathrin-mediated endocytosis, clathrin-coated vesicle formation, SNARE sorting, and endosomal/synaptic vesicle trafficking.
GO:0030136 clathrin-coated vesicle
IMP
PMID:25898166
CALM regulates clathrin-coated vesicle size and maturation b... 		ACCEPT
Summary: This vesicle/coated-pit term is consistent with PICALM acting at clathrin-coated pits and clathrin-coated vesicle intermediates.
Reason: This location is consistent with PICALM/CALM recruitment to cytosolic membrane interfaces used for clathrin-mediated endocytosis, clathrin-coated vesicle formation, SNARE sorting, and endosomal/synaptic vesicle trafficking.
GO:0045334 clathrin-coated endocytic vesicle
NAS
PMID:25898166
CALM regulates clathrin-coated vesicle size and maturation b... 		ACCEPT
Summary: This vesicle/coated-pit term is consistent with PICALM acting at clathrin-coated pits and clathrin-coated vesicle intermediates.
Reason: This location is consistent with PICALM/CALM recruitment to cytosolic membrane interfaces used for clathrin-mediated endocytosis, clathrin-coated vesicle formation, SNARE sorting, and endosomal/synaptic vesicle trafficking.
GO:0097494 regulation of vesicle size
IMP
PMID:25898166
CALM regulates clathrin-coated vesicle size and maturation b... 		ACCEPT
Summary: PICALM regulates clathrin-coated vesicle size, maturation, and membrane curvature through its PIP2-bound ANTH/amphipathic-helix module.
Reason: This term aligns with the core PICALM/CALM role as a phosphoinositide-binding clathrin adaptor that organizes clathrin-coated pits/vesicles, controls vesicle curvature and maturation, and sorts endocytic cargo including small R-SNAREs.
GO:0097753 membrane bending
IMP
PMID:25898166
CALM regulates clathrin-coated vesicle size and maturation b... 		ACCEPT
Summary: PICALM regulates clathrin-coated vesicle size, maturation, and membrane curvature through its PIP2-bound ANTH/amphipathic-helix module.
Reason: This term aligns with the core PICALM/CALM role as a phosphoinositide-binding clathrin adaptor that organizes clathrin-coated pits/vesicles, controls vesicle curvature and maturation, and sorts endocytic cargo including small R-SNAREs.
GO:0007611 learning or memory
ISS
PMID:26005850
Central role for PICALM in amyloid-β blood-brain barrier tra... 		KEEP AS NON CORE
Summary: This annotation is supported or plausible for a specific cellular or disease context, but it is not the primary PICALM clathrin/SNARE adaptor function.
Reason: Retain as non-core because the annotation is supported or plausible but represents a cargo-specific, disease-model, endothelial, iron-homeostasis, nuclear/leukemia, or downstream phenotype rather than the primary clathrin/SNARE adaptor function.
GO:1902003 regulation of amyloid-beta formation
ISS NOT
PMID:26005850
Central role for PICALM in amyloid-β blood-brain barrier tra... 		ACCEPT
Summary: This is a NOT annotation for regulation of amyloid-beta formation; it should be retained because the cited disease-model evidence supports amyloid-beta clearance/transcytosis rather than amyloid-beta production by PICALM.
Reason: The NOT annotation is consistent with evidence that the referenced study separated PICALM-dependent amyloid-beta clearance from amyloid-beta production/formation.
GO:1903077 negative regulation of protein localization to plasma membrane
IMP
PMID:21221849
CALM, a clathrin assembly protein, influences cell surface G... 		KEEP AS NON CORE
Summary: The GluR2/postsynaptic trafficking evidence is plausible but cargo-specific and not the main PICALM clathrin coat/SNARE sorting function.
Reason: Retain as non-core because the annotation is supported or plausible but represents a cargo-specific, disease-model, endothelial, iron-homeostasis, nuclear/leukemia, or downstream phenotype rather than the primary clathrin/SNARE adaptor function.
GO:2000009 negative regulation of protein localization to cell surface
IMP
PMID:21221849
CALM, a clathrin assembly protein, influences cell surface G... 		KEEP AS NON CORE
Summary: The GluR2/postsynaptic trafficking evidence is plausible but cargo-specific and not the main PICALM clathrin coat/SNARE sorting function.
Reason: Retain as non-core because the annotation is supported or plausible but represents a cargo-specific, disease-model, endothelial, iron-homeostasis, nuclear/leukemia, or downstream phenotype rather than the primary clathrin/SNARE adaptor function.
GO:0005769 early endosome
IDA
PMID:26005850
Central role for PICALM in amyloid-β blood-brain barrier tra... 		ACCEPT
Summary: This endosomal/cargo-trafficking term is consistent with PICALM-mediated sorting of endocytic cargo between plasma membrane and endosomal compartments.
Reason: This location is consistent with PICALM/CALM recruitment to cytosolic membrane interfaces used for clathrin-mediated endocytosis, clathrin-coated vesicle formation, SNARE sorting, and endosomal/synaptic vesicle trafficking.
GO:0070381 endosome to plasma membrane transport vesicle
IDA
PMID:26005850
Central role for PICALM in amyloid-β blood-brain barrier tra... 		ACCEPT
Summary: This endosomal/cargo-trafficking term is consistent with PICALM-mediated sorting of endocytic cargo between plasma membrane and endosomal compartments.
Reason: This location is consistent with PICALM/CALM recruitment to cytosolic membrane interfaces used for clathrin-mediated endocytosis, clathrin-coated vesicle formation, SNARE sorting, and endosomal/synaptic vesicle trafficking.
GO:0009986 cell surface
IDA
PMID:26005850
Central role for PICALM in amyloid-β blood-brain barrier tra... 		ACCEPT
Summary: This localization/process is consistent with PICALM acting at cytosolic membrane interfaces for clathrin-mediated endocytosis and vesicle trafficking.
Reason: This location is consistent with PICALM/CALM recruitment to cytosolic membrane interfaces used for clathrin-mediated endocytosis, clathrin-coated vesicle formation, SNARE sorting, and endosomal/synaptic vesicle trafficking.
GO:0005829 cytosol
TAS
Reactome:R-HSA-8867613 		ACCEPT
Summary: This localization/process is consistent with PICALM acting at cytosolic membrane interfaces for clathrin-mediated endocytosis and vesicle trafficking.
Reason: This location is consistent with PICALM/CALM recruitment to cytosolic membrane interfaces used for clathrin-mediated endocytosis, clathrin-coated vesicle formation, SNARE sorting, and endosomal/synaptic vesicle trafficking.
GO:0005829 cytosol
TAS
Reactome:R-HSA-8867754 		ACCEPT
Summary: This localization/process is consistent with PICALM acting at cytosolic membrane interfaces for clathrin-mediated endocytosis and vesicle trafficking.
Reason: This location is consistent with PICALM/CALM recruitment to cytosolic membrane interfaces used for clathrin-mediated endocytosis, clathrin-coated vesicle formation, SNARE sorting, and endosomal/synaptic vesicle trafficking.
GO:0005829 cytosol
TAS
Reactome:R-HSA-8867756 		ACCEPT
Summary: This localization/process is consistent with PICALM acting at cytosolic membrane interfaces for clathrin-mediated endocytosis and vesicle trafficking.
Reason: This location is consistent with PICALM/CALM recruitment to cytosolic membrane interfaces used for clathrin-mediated endocytosis, clathrin-coated vesicle formation, SNARE sorting, and endosomal/synaptic vesicle trafficking.
GO:0005829 cytosol
TAS
Reactome:R-HSA-8868071 		ACCEPT
Summary: This localization/process is consistent with PICALM acting at cytosolic membrane interfaces for clathrin-mediated endocytosis and vesicle trafficking.
Reason: This location is consistent with PICALM/CALM recruitment to cytosolic membrane interfaces used for clathrin-mediated endocytosis, clathrin-coated vesicle formation, SNARE sorting, and endosomal/synaptic vesicle trafficking.
GO:0005829 cytosol
TAS
Reactome:R-HSA-8868072 		ACCEPT
Summary: This localization/process is consistent with PICALM acting at cytosolic membrane interfaces for clathrin-mediated endocytosis and vesicle trafficking.
Reason: This location is consistent with PICALM/CALM recruitment to cytosolic membrane interfaces used for clathrin-mediated endocytosis, clathrin-coated vesicle formation, SNARE sorting, and endosomal/synaptic vesicle trafficking.
GO:0005829 cytosol
TAS
Reactome:R-HSA-8868230 		ACCEPT
Summary: This localization/process is consistent with PICALM acting at cytosolic membrane interfaces for clathrin-mediated endocytosis and vesicle trafficking.
Reason: This location is consistent with PICALM/CALM recruitment to cytosolic membrane interfaces used for clathrin-mediated endocytosis, clathrin-coated vesicle formation, SNARE sorting, and endosomal/synaptic vesicle trafficking.
GO:0005829 cytosol
TAS
Reactome:R-HSA-8868236 		ACCEPT
Summary: This localization/process is consistent with PICALM acting at cytosolic membrane interfaces for clathrin-mediated endocytosis and vesicle trafficking.
Reason: This location is consistent with PICALM/CALM recruitment to cytosolic membrane interfaces used for clathrin-mediated endocytosis, clathrin-coated vesicle formation, SNARE sorting, and endosomal/synaptic vesicle trafficking.
GO:0005829 cytosol
TAS
Reactome:R-HSA-8868648 		ACCEPT
Summary: This localization/process is consistent with PICALM acting at cytosolic membrane interfaces for clathrin-mediated endocytosis and vesicle trafficking.
Reason: This location is consistent with PICALM/CALM recruitment to cytosolic membrane interfaces used for clathrin-mediated endocytosis, clathrin-coated vesicle formation, SNARE sorting, and endosomal/synaptic vesicle trafficking.
GO:0005829 cytosol
TAS
Reactome:R-HSA-8868651 		ACCEPT
Summary: This localization/process is consistent with PICALM acting at cytosolic membrane interfaces for clathrin-mediated endocytosis and vesicle trafficking.
Reason: This location is consistent with PICALM/CALM recruitment to cytosolic membrane interfaces used for clathrin-mediated endocytosis, clathrin-coated vesicle formation, SNARE sorting, and endosomal/synaptic vesicle trafficking.
GO:0005829 cytosol
TAS
Reactome:R-HSA-8868658 		ACCEPT
Summary: This localization/process is consistent with PICALM acting at cytosolic membrane interfaces for clathrin-mediated endocytosis and vesicle trafficking.
Reason: This location is consistent with PICALM/CALM recruitment to cytosolic membrane interfaces used for clathrin-mediated endocytosis, clathrin-coated vesicle formation, SNARE sorting, and endosomal/synaptic vesicle trafficking.
GO:0005829 cytosol
TAS
Reactome:R-HSA-8868659 		ACCEPT
Summary: This localization/process is consistent with PICALM acting at cytosolic membrane interfaces for clathrin-mediated endocytosis and vesicle trafficking.
Reason: This location is consistent with PICALM/CALM recruitment to cytosolic membrane interfaces used for clathrin-mediated endocytosis, clathrin-coated vesicle formation, SNARE sorting, and endosomal/synaptic vesicle trafficking.
GO:0005829 cytosol
TAS
Reactome:R-HSA-8868660 		ACCEPT
Summary: This localization/process is consistent with PICALM acting at cytosolic membrane interfaces for clathrin-mediated endocytosis and vesicle trafficking.
Reason: This location is consistent with PICALM/CALM recruitment to cytosolic membrane interfaces used for clathrin-mediated endocytosis, clathrin-coated vesicle formation, SNARE sorting, and endosomal/synaptic vesicle trafficking.
GO:0005829 cytosol
TAS
Reactome:R-HSA-8868661 		ACCEPT
Summary: This localization/process is consistent with PICALM acting at cytosolic membrane interfaces for clathrin-mediated endocytosis and vesicle trafficking.
Reason: This location is consistent with PICALM/CALM recruitment to cytosolic membrane interfaces used for clathrin-mediated endocytosis, clathrin-coated vesicle formation, SNARE sorting, and endosomal/synaptic vesicle trafficking.
GO:0005829 cytosol
TAS
Reactome:R-HSA-8869438 		ACCEPT
Summary: This localization/process is consistent with PICALM acting at cytosolic membrane interfaces for clathrin-mediated endocytosis and vesicle trafficking.
Reason: This location is consistent with PICALM/CALM recruitment to cytosolic membrane interfaces used for clathrin-mediated endocytosis, clathrin-coated vesicle formation, SNARE sorting, and endosomal/synaptic vesicle trafficking.
GO:0005829 cytosol
TAS
Reactome:R-HSA-8871193 		ACCEPT
Summary: This localization/process is consistent with PICALM acting at cytosolic membrane interfaces for clathrin-mediated endocytosis and vesicle trafficking.
Reason: This location is consistent with PICALM/CALM recruitment to cytosolic membrane interfaces used for clathrin-mediated endocytosis, clathrin-coated vesicle formation, SNARE sorting, and endosomal/synaptic vesicle trafficking.
GO:0005829 cytosol
TAS
Reactome:R-HSA-8871194 		ACCEPT
Summary: This localization/process is consistent with PICALM acting at cytosolic membrane interfaces for clathrin-mediated endocytosis and vesicle trafficking.
Reason: This location is consistent with PICALM/CALM recruitment to cytosolic membrane interfaces used for clathrin-mediated endocytosis, clathrin-coated vesicle formation, SNARE sorting, and endosomal/synaptic vesicle trafficking.
GO:0016020 membrane
HDA
PMID:19946888
Defining the membrane proteome of NK cells. 		ACCEPT
Summary: This localization/process is consistent with PICALM acting at cytosolic membrane interfaces for clathrin-mediated endocytosis and vesicle trafficking.
Reason: This location is consistent with PICALM/CALM recruitment to cytosolic membrane interfaces used for clathrin-mediated endocytosis, clathrin-coated vesicle formation, SNARE sorting, and endosomal/synaptic vesicle trafficking.
GO:0016188 synaptic vesicle maturation
ISS
GO_REF:0000024 		ACCEPT
Summary: This synaptic-vesicle/presynaptic term is consistent with PICALM/AP180-family SNARE sorting and synaptic vesicle trafficking biology.
Reason: This term aligns with the core PICALM/CALM role as a phosphoinositide-binding clathrin adaptor that organizes clathrin-coated pits/vesicles, controls vesicle curvature and maturation, and sorts endocytic cargo including small R-SNAREs.
GO:0031982 vesicle
ISS
GO_REF:0000024 		ACCEPT
Summary: This vesicle/coated-pit term is consistent with PICALM acting at clathrin-coated pits and clathrin-coated vesicle intermediates.
Reason: This location is consistent with PICALM/CALM recruitment to cytosolic membrane interfaces used for clathrin-mediated endocytosis, clathrin-coated vesicle formation, SNARE sorting, and endosomal/synaptic vesicle trafficking.
GO:0005515 protein binding
IPI
PMID:23382074
A high-confidence interaction map identifies SIRT1 as a medi... 		MARK AS OVER ANNOTATED
Summary: The interaction evidence may be real, but generic protein binding is not informative for PICALM because specific clathrin, clathrin heavy chain, SNARE, phosphoinositide, and cargo-adaptor annotations are available.
Reason: This is less informative or less direct than the specific PICALM functions supported by the evidence; prefer clathrin, clathrin heavy chain, SNARE, phosphoinositide, and cargo-trafficking annotations where applicable.
GO:1902004 positive regulation of amyloid-beta formation
IMP
PMID:24577224
Decreased CALM expression reduces Aβ42 to total Aβ ratio thr... 		KEEP AS NON CORE
Summary: The gamma-secretase/APP processing annotation is supported as a cargo-specific consequence of CALM-dependent clathrin-mediated endocytosis, not as a separate catalytic activity.
Reason: Retain as non-core because the annotation is supported or plausible but represents a cargo-specific, disease-model, endothelial, iron-homeostasis, nuclear/leukemia, or downstream phenotype rather than the primary clathrin/SNARE adaptor function.
GO:0010629 negative regulation of gene expression
IMP
PMID:22952941
The PICALM protein plays a key role in iron homeostasis and ... 		KEEP AS NON CORE
Summary: The iron-homeostasis and linked expression/proliferation phenotypes are supported, but they arise downstream of transferrin receptor endocytosis rather than defining the primary molecular role.
Reason: Retain as non-core because the annotation is supported or plausible but represents a cargo-specific, disease-model, endothelial, iron-homeostasis, nuclear/leukemia, or downstream phenotype rather than the primary clathrin/SNARE adaptor function.
GO:0072583 clathrin-dependent endocytosis
IMP
PMID:22952941
The PICALM protein plays a key role in iron homeostasis and ... 		ACCEPT
Summary: This endocytosis/receptor-internalization term captures the core PICALM role in clathrin-mediated internalization and coated-vesicle maturation.
Reason: This term aligns with the core PICALM/CALM role as a phosphoinositide-binding clathrin adaptor that organizes clathrin-coated pits/vesicles, controls vesicle curvature and maturation, and sorts endocytic cargo including small R-SNAREs.
GO:0035459 vesicle cargo loading
IMP
PMID:24577224
Decreased CALM expression reduces Aβ42 to total Aβ ratio thr... 		ACCEPT
Summary: This endosomal/cargo-trafficking term is consistent with PICALM-mediated sorting of endocytic cargo between plasma membrane and endosomal compartments.
Reason: This term aligns with the core PICALM/CALM role as a phosphoinositide-binding clathrin adaptor that organizes clathrin-coated pits/vesicles, controls vesicle curvature and maturation, and sorts endocytic cargo including small R-SNAREs.
GO:0043025 neuronal cell body
IDA
PMID:23589030
Clathrin adaptor CALM/PICALM is associated with neurofibrill... 		KEEP AS NON CORE
Summary: The tau/neurofibrillary-tangle evidence is Alzheimer-relevant, but it reflects pathology-associated localization or binding rather than the main clathrin/SNARE adaptor role.
Reason: Retain as non-core because the annotation is supported or plausible but represents a cargo-specific, disease-model, endothelial, iron-homeostasis, nuclear/leukemia, or downstream phenotype rather than the primary clathrin/SNARE adaptor function.
GO:0072583 clathrin-dependent endocytosis
IMP
PMID:24577224
Decreased CALM expression reduces Aβ42 to total Aβ ratio thr... 		ACCEPT
Summary: This endocytosis/receptor-internalization term captures the core PICALM role in clathrin-mediated internalization and coated-vesicle maturation.
Reason: This term aligns with the core PICALM/CALM role as a phosphoinositide-binding clathrin adaptor that organizes clathrin-coated pits/vesicles, controls vesicle curvature and maturation, and sorts endocytic cargo including small R-SNAREs.
GO:0097418 neurofibrillary tangle
IMP
PMID:23589030
Clathrin adaptor CALM/PICALM is associated with neurofibrill... 		KEEP AS NON CORE
Summary: The tau/neurofibrillary-tangle evidence is Alzheimer-relevant, but it reflects pathology-associated localization or binding rather than the main clathrin/SNARE adaptor role.
Reason: Retain as non-core because the annotation is supported or plausible but represents a cargo-specific, disease-model, endothelial, iron-homeostasis, nuclear/leukemia, or downstream phenotype rather than the primary clathrin/SNARE adaptor function.
GO:0031623 receptor internalization
IMP
PMID:14985334
Analysis of clathrin-mediated endocytosis of epidermal growt... 		ACCEPT
Summary: This endocytosis/receptor-internalization term captures the core PICALM role in clathrin-mediated internalization and coated-vesicle maturation.
Reason: This term aligns with the core PICALM/CALM role as a phosphoinositide-binding clathrin adaptor that organizes clathrin-coated pits/vesicles, controls vesicle curvature and maturation, and sorts endocytic cargo including small R-SNAREs.
GO:0005515 protein binding
IPI
PMID:16491119
The novel CALM interactor CATS influences the subcellular lo... 		MARK AS OVER ANNOTATED
Summary: The interaction evidence may be real, but generic protein binding is not informative for PICALM because specific clathrin, clathrin heavy chain, SNARE, phosphoinositide, and cargo-adaptor annotations are available.
Reason: This is less informative or less direct than the specific PICALM functions supported by the evidence; prefer clathrin, clathrin heavy chain, SNARE, phosphoinositide, and cargo-trafficking annotations where applicable.
GO:0005634 nucleus
IDA
PMID:16491119
The novel CALM interactor CATS influences the subcellular lo... 		KEEP AS NON CORE
Summary: Nuclear localization and transcriptional effects are context-specific, mainly from nuclear shuttling or leukemia-fusion/interactor biology, and are not the principal PICALM function.
Reason: Retain as non-core because the annotation is supported or plausible but represents a cargo-specific, disease-model, endothelial, iron-homeostasis, nuclear/leukemia, or downstream phenotype rather than the primary clathrin/SNARE adaptor function.
GO:0045893 positive regulation of DNA-templated transcription
IDA
PMID:11425879
Nucleocytoplasmic shuttling of endocytic proteins. 		KEEP AS NON CORE
Summary: Nuclear localization and transcriptional effects are context-specific, mainly from nuclear shuttling or leukemia-fusion/interactor biology, and are not the principal PICALM function.
Reason: Retain as non-core because the annotation is supported or plausible but represents a cargo-specific, disease-model, endothelial, iron-homeostasis, nuclear/leukemia, or downstream phenotype rather than the primary clathrin/SNARE adaptor function.
GO:0032050 clathrin heavy chain binding
IDA
PMID:10436022
Clathrin assembly lymphoid myeloid leukemia (CALM) protein: ... 		ACCEPT
Summary: Direct clathrin/clathrin-heavy-chain binding is central to PICALM recruitment and clathrin-coated pit/vesicle assembly.
Reason: This term aligns with the core PICALM/CALM role as a phosphoinositide-binding clathrin adaptor that organizes clathrin-coated pits/vesicles, controls vesicle curvature and maturation, and sorts endocytic cargo including small R-SNAREs.
GO:0032880 regulation of protein localization
IDA
PMID:10436022
Clathrin assembly lymphoid myeloid leukemia (CALM) protein: ... 		ACCEPT
Summary: This localization/process is consistent with PICALM acting at cytosolic membrane interfaces for clathrin-mediated endocytosis and vesicle trafficking.
Reason: This term aligns with the core PICALM/CALM role as a phosphoinositide-binding clathrin adaptor that organizes clathrin-coated pits/vesicles, controls vesicle curvature and maturation, and sorts endocytic cargo including small R-SNAREs.
GO:0048261 negative regulation of receptor-mediated endocytosis
IDA
PMID:10436022
Clathrin assembly lymphoid myeloid leukemia (CALM) protein: ... 		MARK AS OVER ANNOTATED
Summary: The negative regulation term reflects dominant-negative overexpression effects on receptor endocytosis, whereas loss-of-function and rescue studies support a normal positive/core role in clathrin-mediated internalization.
Reason: The annotation is not simply wrong, but it over-emphasizes an overexpression phenotype and can misrepresent normal PICALM biology; receptor-mediated endocytosis and clathrin-dependent endocytosis capture the core process better.
GO:0016197 endosomal transport
IMP
PMID:16262731
Effect of clathrin assembly lymphoid myeloid leukemia protei... 		ACCEPT
Summary: This endosomal/cargo-trafficking term is consistent with PICALM-mediated sorting of endocytic cargo between plasma membrane and endosomal compartments.
Reason: This term aligns with the core PICALM/CALM role as a phosphoinositide-binding clathrin adaptor that organizes clathrin-coated pits/vesicles, controls vesicle curvature and maturation, and sorts endocytic cargo including small R-SNAREs.
GO:0030276 clathrin binding
IDA
PMID:16262731
Effect of clathrin assembly lymphoid myeloid leukemia protei... 		ACCEPT
Summary: Direct clathrin/clathrin-heavy-chain binding is central to PICALM recruitment and clathrin-coated pit/vesicle assembly.
Reason: This term aligns with the core PICALM/CALM role as a phosphoinositide-binding clathrin adaptor that organizes clathrin-coated pits/vesicles, controls vesicle curvature and maturation, and sorts endocytic cargo including small R-SNAREs.
GO:0048268 clathrin coat assembly
IMP
PMID:16262731
Effect of clathrin assembly lymphoid myeloid leukemia protei... 		ACCEPT
Summary: PICALM is required for orderly clathrin coat and coated-bud formation at the plasma membrane.
Reason: This term aligns with the core PICALM/CALM role as a phosphoinositide-binding clathrin adaptor that organizes clathrin-coated pits/vesicles, controls vesicle curvature and maturation, and sorts endocytic cargo including small R-SNAREs.
GO:0030100 regulation of endocytosis
IMP
PMID:18182011
Evidence for CALM in directing VAMP2 trafficking. 		ACCEPT
Summary: This endocytosis/receptor-internalization term captures the core PICALM role in clathrin-mediated internalization and coated-vesicle maturation.
Reason: This term aligns with the core PICALM/CALM role as a phosphoinositide-binding clathrin adaptor that organizes clathrin-coated pits/vesicles, controls vesicle curvature and maturation, and sorts endocytic cargo including small R-SNAREs.
GO:0042734 presynaptic membrane
ISS
GO_REF:0000024 		ACCEPT
Summary: This synaptic-vesicle/presynaptic term is consistent with PICALM/AP180-family SNARE sorting and synaptic vesicle trafficking biology.
Reason: This location is consistent with PICALM/CALM recruitment to cytosolic membrane interfaces used for clathrin-mediated endocytosis, clathrin-coated vesicle formation, SNARE sorting, and endosomal/synaptic vesicle trafficking.
GO:0045211 postsynaptic membrane
ISS
GO_REF:0000024 		KEEP AS NON CORE
Summary: The GluR2/postsynaptic trafficking evidence is plausible but cargo-specific and not the main PICALM clathrin coat/SNARE sorting function.
Reason: Retain as non-core because the annotation is supported or plausible but represents a cargo-specific, disease-model, endothelial, iron-homeostasis, nuclear/leukemia, or downstream phenotype rather than the primary clathrin/SNARE adaptor function.
GO:0048471 perinuclear region of cytoplasm
ISS
GO_REF:0000024 		KEEP AS NON CORE
Summary: This annotation is supported or plausible for a specific cellular or disease context, but it is not the primary PICALM clathrin/SNARE adaptor function.
Reason: Retain as non-core because the annotation is supported or plausible but represents a cargo-specific, disease-model, endothelial, iron-homeostasis, nuclear/leukemia, or downstream phenotype rather than the primary clathrin/SNARE adaptor function.
GO:0005545 1-phosphatidylinositol binding
ISS
GO_REF:0000024 		ACCEPT
Summary: PICALM/CALM uses its ANTH domain to bind phosphoinositides/PIP2 at clathrin-coated membrane sites, anchoring its endocytic adaptor and curvature functions.
Reason: This term aligns with the core PICALM/CALM role as a phosphoinositide-binding clathrin adaptor that organizes clathrin-coated pits/vesicles, controls vesicle curvature and maturation, and sorts endocytic cargo including small R-SNAREs.
GO:0005905 clathrin-coated pit
IDA
PMID:10436022
Clathrin assembly lymphoid myeloid leukemia (CALM) protein: ... 		ACCEPT
Summary: This vesicle/coated-pit term is consistent with PICALM acting at clathrin-coated pits and clathrin-coated vesicle intermediates.
Reason: This location is consistent with PICALM/CALM recruitment to cytosolic membrane interfaces used for clathrin-mediated endocytosis, clathrin-coated vesicle formation, SNARE sorting, and endosomal/synaptic vesicle trafficking.
GO:0006898 receptor-mediated endocytosis
IDA
PMID:10436022
Clathrin assembly lymphoid myeloid leukemia (CALM) protein: ... 		ACCEPT
Summary: This endocytosis/receptor-internalization term captures the core PICALM role in clathrin-mediated internalization and coated-vesicle maturation.
Reason: This term aligns with the core PICALM/CALM role as a phosphoinositide-binding clathrin adaptor that organizes clathrin-coated pits/vesicles, controls vesicle curvature and maturation, and sorts endocytic cargo including small R-SNAREs.
GO:0030276 clathrin binding
IDA
PMID:10436022
Clathrin assembly lymphoid myeloid leukemia (CALM) protein: ... 		ACCEPT
Summary: Direct clathrin/clathrin-heavy-chain binding is central to PICALM recruitment and clathrin-coated pit/vesicle assembly.
Reason: This term aligns with the core PICALM/CALM role as a phosphoinositide-binding clathrin adaptor that organizes clathrin-coated pits/vesicles, controls vesicle curvature and maturation, and sorts endocytic cargo including small R-SNAREs.
GO:0016192 vesicle-mediated transport
TAS
PMID:8643484
The t(10;11)(p13;q14) in the U937 cell line results in the f... 		ACCEPT
Summary: This vesicle/coated-pit term is consistent with PICALM acting at clathrin-coated pits and clathrin-coated vesicle intermediates.
Reason: This term aligns with the core PICALM/CALM role as a phosphoinositide-binding clathrin adaptor that organizes clathrin-coated pits/vesicles, controls vesicle curvature and maturation, and sorts endocytic cargo including small R-SNAREs.
GO:0065003 protein-containing complex assembly
TAS
PMID:8643484
The t(10;11)(p13;q14) in the U937 cell line results in the f... 		MODIFY
Summary: The generic protein-containing complex assembly annotation is too broad for PICALM; the supported complex-assembly role is clathrin coat assembly.
Reason: The source publication identifies CALM as a clathrin assembly protein family member, and later direct evidence supports clathrin coat formation; use the specific clathrin coat assembly term instead of a generic complex-assembly term.
Proposed replacements: clathrin coat assembly

Core Functions

PICALM binds PIP2/phosphoinositide-rich cytosolic membrane surfaces through its ANTH domain and N-terminal amphipathic helix, positioning the adaptor at clathrin-coated pits where it senses and drives curvature during coated-vesicle maturation.

Molecular Function:
phosphatidylinositol-4,5-bisphosphate binding
Directly Involved In:
membrane bending regulation of vesicle size vesicle budding from membrane clathrin-dependent endocytosis
Cellular Locations:
clathrin-coated pit clathrin-coated vesicle plasma membrane cytosol
Supporting Evidence:
  • PMID:25898166
    CALM is thus a major factor in controlling CCV size and maturation
  • PMID:25898166
    Here we show that CALM possesses an N-terminal amphipathic helix that regulates CCP/CCV size and maturation and hence endocytic rate

PICALM binds clathrin heavy chain and AP-2-associated endocytic machinery to promote clathrin recruitment, clathrin coat assembly, and receptor/cargo internalization at plasma membrane coated pits and related Golgi/endosomal sites.

Molecular Function:
clathrin binding
Directly Involved In:
clathrin coat assembly clathrin-dependent endocytosis receptor-mediated endocytosis receptor internalization
Cellular Locations:
clathrin-coated pit clathrin-coated vesicle Golgi apparatus
Supporting Evidence:
  • PMID:10436022
    the clathrin heavy chain is the major binding partner of CALM
  • PMID:10436022
    Altogether, the data suggest that CALM is an important component of coated pit internalization machinery
  • PMID:16262731
    critical role for CALM in the regulation and orderly progression of coated bud formation at the plasma membrane

PICALM directly recognizes small R-SNARE cargoes, including VAMP2, VAMP3, and VAMP8, and sorts them into endocytic clathrin-coated vesicles for cycling between the plasma membrane and endosomal/synaptic-vesicle compartments.

Molecular Function:
SNARE binding
Directly Involved In:
clathrin-dependent endocytosis vesicle cargo loading synaptic vesicle maturation endosomal transport
Cellular Locations:
synaptic vesicle presynaptic membrane endosome to plasma membrane transport vesicle early endosome clathrin-coated vesicle
Supporting Evidence:

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: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:0000111
Gene Ontology annotations Inferred by Curator (IC) using at least one Inferred by Sequence Similarity (ISS) annotation to support the inference
GO_REF:0000117
Electronic Gene Ontology annotations created by ARBA machine learning models
GO_REF:0000120
Combined Automated Annotation using Multiple IEA Methods
PMID:10436022
Clathrin assembly lymphoid myeloid leukemia (CALM) protein: localization in endocytic-coated pits, interactions with clathrin, and the impact of overexpression on clathrin-mediated traffic.
PMID:11425879
Nucleocytoplasmic shuttling of endocytic proteins.
PMID:14985334
Analysis of clathrin-mediated endocytosis of epidermal growth factor receptor by RNA interference.
PMID:16262731
Effect of clathrin assembly lymphoid myeloid leukemia protein depletion on clathrin coat formation.
PMID:16491119
The novel CALM interactor CATS influences the subcellular localization of the leukemogenic fusion protein CALM/AF10.
PMID:18182011
Evidence for CALM in directing VAMP2 trafficking.
PMID:19946888
Defining the membrane proteome of NK cells.
PMID:21221849
CALM, a clathrin assembly protein, influences cell surface GluR2 abundance.
PMID:22118466
The molecular basis for the endocytosis of small R-SNAREs by the clathrin adaptor CALM.
PMID:22829078
FHL2 interacts with CALM and is highly expressed in acute erythroid leukemia.
PMID:22952941
The PICALM protein plays a key role in iron homeostasis and cell proliferation.
PMID:23382074
A high-confidence interaction map identifies SIRT1 as a mediator of acetylation of USP22 and the SAGA coactivator complex.
PMID:23589030
Clathrin adaptor CALM/PICALM is associated with neurofibrillary tangles and is cleaved in Alzheimer's brains.
PMID:24577224
Decreased CALM expression reduces Aβ42 to total Aβ ratio through clathrin-mediated endocytosis of γ-secretase.
PMID:25468996
E-cadherin interactome complexity and robustness resolved by quantitative proteomics.
PMID:25898166
CALM regulates clathrin-coated vesicle size and maturation by directly sensing and driving membrane curvature.
PMID:26005850
Central role for PICALM in amyloid-β blood-brain barrier transcytosis and clearance.
PMID:26496610
A human interactome in three quantitative dimensions organized by stoichiometries and abundances.
PMID:35044719
Proteome-scale mapping of binding sites in the unstructured regions of the human proteome.
PMID:8643484
The t(10;11)(p13;q14) in the U937 cell line results in the fusion of the AF10 gene and CALM, encoding a new member of the AP-3 clathrin assembly protein family.
Reactome:R-HSA-8867613
PICALM binds R-SNAREs
Reactome:R-HSA-8867754
F- and N- BAR domain proteins bind the clathrin-coated pit
Reactome:R-HSA-8867756
CLASP proteins and cargo are recruited to the nascent clathrin-coated pit
Reactome:R-HSA-8868071
Clathrin recruits PIK3C2A
Reactome:R-HSA-8868072
Clathrin-associated PIK3C2A phosphorylates PI(4)P to PI(3,4)P2
Reactome:R-HSA-8868230
SNX9 recruits components of the actin polymerizing machinery
Reactome:R-HSA-8868236
BAR domain proteins recruit dynamin
Reactome:R-HSA-8868648
SYNJ hydrolyze PI(4,5)P2 to PI(4)P
Reactome:R-HSA-8868651
Endophilins recruit synaptojanins to the clathrin-coated pit
Reactome:R-HSA-8868658
HSPA8-mediated ATP hydrolysis promotes vesicle uncoating
Reactome:R-HSA-8868659
Clathrin recruits auxilins to the clathrin-coated vesicle
Reactome:R-HSA-8868660
Auxilin recruits HSPA8:ATP to the clathrin-coated vesicle
Reactome:R-HSA-8868661
Dynamin-mediated GTP hydrolysis promotes vesicle scission
Reactome:R-HSA-8869438
Dissociation of clathrin-associated proteins
Reactome:R-HSA-8871193
Dissociation of AAK1 and dephosphorylation of AP-2 mu2
Reactome:R-HSA-8871194
RAB5 and GAPVD1 bind AP-2

Suggested Questions for Experts

Q: Should amyloid-beta/LRP1 transcytosis annotations be represented as cargo-specific receptor internalization/transcytosis rather than direct amyloid-beta binding by PICALM?

Suggested experts: Alzheimer BBB trafficking experts, GO endocytosis curators

Q: Which PICALM isoforms or tissue contexts should be distinguished for neuronal SNARE sorting, endothelial amyloid-beta clearance, erythroid transferrin receptor uptake, and nuclear/leukemia-associated localization?

Suggested experts: PICALM/CALM domain experts, GO isoform annotation curators

Suggested Experiments

Experiment: Rescue PICALM-null human neurons, endothelial cells, and erythroid precursors with endogenous-level wild-type, PIP2-binding-defective, clathrin-binding-defective, and SNARE-binding-defective PICALM variants, then quantify clathrin-coated pit maturation, VAMP cargo sorting, LRP1/amyloid-beta transcytosis, and transferrin receptor uptake.

Hypothesis: PIP2/membrane-curvature, clathrin, and SNARE-binding modules make separable contributions to shared endocytic adaptor function and tissue-specific cargo phenotypes.

Type: endogenous-rescue separation-of-function trafficking assay

Experiment: Test whether PICALM directly binds amyloid-beta or instead binds LRP1/cargo complexes during endothelial transcytosis using purified components, LRP1-tail mutants, and live-cell cargo uptake assays.

Hypothesis: PICALM promotes amyloid-beta clearance primarily by recognizing LRP1/cargo endocytic machinery rather than by direct amyloid-beta binding.

Type: cargo-binding and endothelial transcytosis mechanism assay

📚 Additional Documentation

Notes

(PICALM-notes.md)

PICALM curation notes

2026-06-19

  • Deep-research attempt with just deep-research-falcon human PICALM --fallback perplexity-lite timed out after 180 seconds with no generated research artifact, so this manual review uses cached UniProt, GOA, Reactome, and publication evidence.
  • PICALM/CALM is a phosphatidylinositol-binding clathrin assembly adaptor. The core function is clathrin-mediated endocytosis: CALM binds clathrin heavy chain, localizes to plasma membrane clathrin-coated pits, and affects transferrin/EGF receptor endocytosis and clathrin recruitment PMID:10436022.
  • Depletion data support a direct role in clathrin coat formation rather than just a passive localization marker. CALM knockdown produced enlarged/abnormal clathrin structures and the abstract concludes a critical role in orderly coated bud formation at the plasma membrane PMID:16262731.
  • The ANTH/PIP2-linked membrane-curvature function is core. CALM depletion altered CCP/CCV maturation and size, and the N-terminal helix was required for rescue of normal vesicle size/maturation PMID:25898166.
  • SNARE cargo sorting is core. CALM/PICALM directly binds small R-SNAREs VAMP8, VAMP3, and VAMP2 and is needed for their endocytosis, explaining the SNARE binding, synaptic vesicle, and vesicle cargo loading annotations PMID:22118466.
  • Alzheimer and brain endothelial annotations are important but mostly non-core relative to the evolved adapter function. PICALM regulates amyloid-beta/LRP1 internalization and transcytosis across BBB endothelial cells, with reduced PICALM in AD endothelium and impaired amyloid-beta efflux in Picalm-deficient mice PMID:26005850. I kept these as non-core disease-context/cargo-specific annotations.
  • APP/gamma-secretase annotations are supported as cargo-specific consequences of clathrin-mediated trafficking, not a separate catalytic role: CALM depletion changes gamma-secretase localization and A-beta species ratio PMID:24577224.
  • Iron-homeostasis annotations are supported by Picalm-deficient MEF and mouse data, but they are downstream of transferrin receptor endocytosis rather than a distinct molecular activity PMID:22952941.
  • Tau/neurofibrillary tangle annotations are Alzheimer-relevant but non-core. The cached abstract supports PICALM association with tau pathology and co-immunoprecipitation with PHF-tau, but this is a pathology interaction rather than the main clathrin/SNARE adaptor role PMID:23589030.
  • Nuclear/transcription/PIMREG/CATS annotations are retained as non-core or over-annotation where generic, because nuclear localization is context-specific and the main evidence frames CATS/PIMREG as changing CALM localization in leukemia-fusion biology PMID:16491119.
  • Generic protein binding and high-throughput cadherin binding annotations are over-annotated; specific binding terms for clathrin, clathrin heavy chain, SNAREs, PIP2/phosphatidylinositol, and LRP1-related cargo context are more informative.

2026-06-20 second-pass audit

The second-pass audit confirmed the existing PICALM review and manual reference metadata. No annotation action changes were needed: PICALM remains curated as an ANTH-domain clathrin/SNARE cargo adaptor for clathrin-mediated endocytosis, with Alzheimer-relevant amyloid-beta/LRP1 trafficking, iron-homeostasis, tau, and nuclear-fusion contexts retained as non-core or over-annotated when they do not describe the core adaptor mechanism.

📄 View Raw YAML

 
id: Q13492
gene_symbol: PICALM
product_type: PROTEIN
status: COMPLETE
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: 'PICALM encodes CALM, a ubiquitously expressed ANTH-domain clathrin adaptor that
  binds phosphatidylinositol phosphates, clathrin, AP-2, and selected cargo proteins to promote
  clathrin-coated pit maturation and clathrin-mediated endocytosis. It localizes mainly to
  cytosolic membrane interfaces including plasma membrane clathrin-coated pits, clathrin-coated
  vesicles, Golgi/endosomal compartments, and synaptic vesicle-related membranes. PICALM helps
  determine clathrin-coated vesicle size and membrane curvature, and it sorts small R-SNAREs
  such as VAMP2, VAMP3, and VAMP8 between the plasma membrane and endosomes. Cargo- and tissue-specific
  consequences include transferrin receptor/iron uptake, AMPA receptor trafficking, gamma-secretase
  and APP-related trafficking, amyloid-beta transcytosis across brain endothelium, and association
  with tau pathology.'
alternative_products:
- name: 1 (Type I)
  id: Q13492-1
- name: 2 (Type II)
  id: Q13492-2
  sequence_note: VSP_004067
- name: '3'
  id: Q13492-3
  sequence_note: VSP_009607, VSP_009608
- name: '4'
  id: Q13492-4
  sequence_note: VSP_044567, VSP_009607
- name: '5'
  id: Q13492-5
  sequence_note: VSP_044568
existing_annotations:
- term:
    id: GO:0072583
    label: clathrin-dependent endocytosis
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: 'This endocytosis/receptor-internalization term captures the core PICALM role
      in clathrin-mediated internalization and coated-vesicle maturation.'
    action: ACCEPT
    reason: This term aligns with the core PICALM/CALM role as a 
      phosphoinositide-binding clathrin adaptor that organizes clathrin-coated 
      pits/vesicles, controls vesicle curvature and maturation, and sorts endocytic 
      cargo including small R-SNAREs.
- term:
    id: GO:0005546
    label: phosphatidylinositol-4,5-bisphosphate binding
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  review:
    summary: 'PICALM/CALM uses its ANTH domain to bind phosphoinositides/PIP2 at clathrin-coated
      membrane sites, anchoring its endocytic adaptor and curvature functions.'
    action: ACCEPT
    reason: This term aligns with the core PICALM/CALM role as a 
      phosphoinositide-binding clathrin adaptor that organizes clathrin-coated 
      pits/vesicles, controls vesicle curvature and maturation, and sorts endocytic 
      cargo including small R-SNAREs.
- term:
    id: GO:0006900
    label: vesicle budding from membrane
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: 'This vesicle/coated-pit term is consistent with PICALM acting at clathrin-coated
      pits and clathrin-coated vesicle intermediates.'
    action: ACCEPT
    reason: This term aligns with the core PICALM/CALM role as a 
      phosphoinositide-binding clathrin adaptor that organizes clathrin-coated 
      pits/vesicles, controls vesicle curvature and maturation, and sorts endocytic 
      cargo including small R-SNAREs.
- term:
    id: GO:0098894
    label: extrinsic component of presynaptic endocytic zone membrane
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: is_active_in
  review:
    summary: 'This localization/process is consistent with PICALM acting at cytosolic membrane
      interfaces for clathrin-mediated endocytosis and vesicle trafficking.'
    action: ACCEPT
    reason: This location is consistent with PICALM/CALM recruitment to cytosolic 
      membrane interfaces used for clathrin-mediated endocytosis, clathrin-coated 
      vesicle formation, SNARE sorting, and endosomal/synaptic vesicle trafficking.
- term:
    id: GO:0005905
    label: clathrin-coated pit
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: is_active_in
  review:
    summary: 'This vesicle/coated-pit term is consistent with PICALM acting at clathrin-coated
      pits and clathrin-coated vesicle intermediates.'
    action: ACCEPT
    reason: This location is consistent with PICALM/CALM recruitment to cytosolic 
      membrane interfaces used for clathrin-mediated endocytosis, clathrin-coated 
      vesicle formation, SNARE sorting, and endosomal/synaptic vesicle trafficking.
- term:
    id: GO:0000149
    label: SNARE binding
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  review:
    summary: 'PICALM directly binds small R-SNAREs such as VAMP2, VAMP3, and VAMP8 and mediates
      their endocytosis.'
    action: ACCEPT
    reason: This term aligns with the core PICALM/CALM role as a 
      phosphoinositide-binding clathrin adaptor that organizes clathrin-coated 
      pits/vesicles, controls vesicle curvature and maturation, and sorts endocytic 
      cargo including small R-SNAREs.
- term:
    id: GO:0030136
    label: clathrin-coated vesicle
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: is_active_in
  review:
    summary: 'This vesicle/coated-pit term is consistent with PICALM acting at clathrin-coated
      pits and clathrin-coated vesicle intermediates.'
    action: ACCEPT
    reason: This location is consistent with PICALM/CALM recruitment to cytosolic 
      membrane interfaces used for clathrin-mediated endocytosis, clathrin-coated 
      vesicle formation, SNARE sorting, and endosomal/synaptic vesicle trafficking.
- term:
    id: GO:0005545
    label: 1-phosphatidylinositol binding
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  review:
    summary: 'PICALM/CALM uses its ANTH domain to bind phosphoinositides/PIP2 at clathrin-coated
      membrane sites, anchoring its endocytic adaptor and curvature functions.'
    action: ACCEPT
    reason: This term aligns with the core PICALM/CALM role as a 
      phosphoinositide-binding clathrin adaptor that organizes clathrin-coated 
      pits/vesicles, controls vesicle curvature and maturation, and sorts endocytic 
      cargo including small R-SNAREs.
- term:
    id: GO:0008021
    label: synaptic vesicle
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: is_active_in
  review:
    summary: 'This synaptic-vesicle/presynaptic term is consistent with PICALM/AP180-family
      SNARE sorting and synaptic vesicle trafficking biology.'
    action: ACCEPT
    reason: This location is consistent with PICALM/CALM recruitment to cytosolic 
      membrane interfaces used for clathrin-mediated endocytosis, clathrin-coated 
      vesicle formation, SNARE sorting, and endosomal/synaptic vesicle trafficking.
- term:
    id: GO:0032050
    label: clathrin heavy chain binding
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  review:
    summary: 'Direct clathrin/clathrin-heavy-chain binding is central to PICALM recruitment
      and clathrin-coated pit/vesicle assembly.'
    action: ACCEPT
    reason: This term aligns with the core PICALM/CALM role as a 
      phosphoinositide-binding clathrin adaptor that organizes clathrin-coated 
      pits/vesicles, controls vesicle curvature and maturation, and sorts endocytic 
      cargo including small R-SNAREs.
- term:
    id: GO:0005543
    label: phospholipid binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: enables
  review:
    summary: 'PICALM/CALM uses its ANTH domain to bind phosphoinositides/PIP2 at clathrin-coated
      membrane sites, anchoring its endocytic adaptor and curvature functions.'
    action: ACCEPT
    reason: This term aligns with the core PICALM/CALM role as a 
      phosphoinositide-binding clathrin adaptor that organizes clathrin-coated 
      pits/vesicles, controls vesicle curvature and maturation, and sorts endocytic 
      cargo including small R-SNAREs.
- term:
    id: GO:0005545
    label: 1-phosphatidylinositol binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: enables
  review:
    summary: 'PICALM/CALM uses its ANTH domain to bind phosphoinositides/PIP2 at clathrin-coated
      membrane sites, anchoring its endocytic adaptor and curvature functions.'
    action: ACCEPT
    reason: This term aligns with the core PICALM/CALM role as a 
      phosphoinositide-binding clathrin adaptor that organizes clathrin-coated 
      pits/vesicles, controls vesicle curvature and maturation, and sorts endocytic 
      cargo including small R-SNAREs.
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: 'Nuclear localization and transcriptional effects are context-specific, mainly
      from nuclear shuttling or leukemia-fusion/interactor biology, and are not the principal
      PICALM function.'
    action: KEEP_AS_NON_CORE
    reason: Retain as non-core because the annotation is supported or plausible but 
      represents a cargo-specific, disease-model, endothelial, iron-homeostasis, 
      nuclear/leukemia, or downstream phenotype rather than the primary clathrin/SNARE 
      adaptor function.
- term:
    id: GO:0005794
    label: Golgi apparatus
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: 'This localization/process is consistent with PICALM acting at cytosolic membrane
      interfaces for clathrin-mediated endocytosis and vesicle trafficking.'
    action: ACCEPT
    reason: This location is consistent with PICALM/CALM recruitment to cytosolic 
      membrane interfaces used for clathrin-mediated endocytosis, clathrin-coated 
      vesicle formation, SNARE sorting, and endosomal/synaptic vesicle trafficking.
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: 'This localization/process is consistent with PICALM acting at cytosolic membrane
      interfaces for clathrin-mediated endocytosis and vesicle trafficking.'
    action: ACCEPT
    reason: This location is consistent with PICALM/CALM recruitment to cytosolic 
      membrane interfaces used for clathrin-mediated endocytosis, clathrin-coated 
      vesicle formation, SNARE sorting, and endosomal/synaptic vesicle trafficking.
- term:
    id: GO:0005905
    label: clathrin-coated pit
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: 'This vesicle/coated-pit term is consistent with PICALM acting at clathrin-coated
      pits and clathrin-coated vesicle intermediates.'
    action: ACCEPT
    reason: This location is consistent with PICALM/CALM recruitment to cytosolic 
      membrane interfaces used for clathrin-mediated endocytosis, clathrin-coated 
      vesicle formation, SNARE sorting, and endosomal/synaptic vesicle trafficking.
- term:
    id: GO:0006897
    label: endocytosis
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  qualifier: involved_in
  review:
    summary: 'This endocytosis/receptor-internalization term captures the core PICALM role
      in clathrin-mediated internalization and coated-vesicle maturation.'
    action: ACCEPT
    reason: This term aligns with the core PICALM/CALM role as a 
      phosphoinositide-binding clathrin adaptor that organizes clathrin-coated 
      pits/vesicles, controls vesicle curvature and maturation, and sorts endocytic 
      cargo including small R-SNAREs.
- term:
    id: GO:0012505
    label: endomembrane system
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  qualifier: located_in
  review:
    summary: 'This localization/process is consistent with PICALM acting at cytosolic membrane
      interfaces for clathrin-mediated endocytosis and vesicle trafficking.'
    action: ACCEPT
    reason: This location is consistent with PICALM/CALM recruitment to cytosolic 
      membrane interfaces used for clathrin-mediated endocytosis, clathrin-coated 
      vesicle formation, SNARE sorting, and endosomal/synaptic vesicle trafficking.
- term:
    id: GO:0016020
    label: membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  qualifier: located_in
  review:
    summary: 'This localization/process is consistent with PICALM acting at cytosolic membrane
      interfaces for clathrin-mediated endocytosis and vesicle trafficking.'
    action: ACCEPT
    reason: This location is consistent with PICALM/CALM recruitment to cytosolic 
      membrane interfaces used for clathrin-mediated endocytosis, clathrin-coated 
      vesicle formation, SNARE sorting, and endosomal/synaptic vesicle trafficking.
- term:
    id: GO:0030136
    label: clathrin-coated vesicle
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: located_in
  review:
    summary: 'This vesicle/coated-pit term is consistent with PICALM acting at clathrin-coated
      pits and clathrin-coated vesicle intermediates.'
    action: ACCEPT
    reason: This location is consistent with PICALM/CALM recruitment to cytosolic 
      membrane interfaces used for clathrin-mediated endocytosis, clathrin-coated 
      vesicle formation, SNARE sorting, and endosomal/synaptic vesicle trafficking.
- term:
    id: GO:0030276
    label: clathrin binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: enables
  review:
    summary: 'Direct clathrin/clathrin-heavy-chain binding is central to PICALM recruitment
      and clathrin-coated pit/vesicle assembly.'
    action: ACCEPT
    reason: This term aligns with the core PICALM/CALM role as a 
      phosphoinositide-binding clathrin adaptor that organizes clathrin-coated 
      pits/vesicles, controls vesicle curvature and maturation, and sorts endocytic 
      cargo including small R-SNAREs.
- term:
    id: GO:0031982
    label: vesicle
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  qualifier: located_in
  review:
    summary: 'This vesicle/coated-pit term is consistent with PICALM acting at clathrin-coated
      pits and clathrin-coated vesicle intermediates.'
    action: ACCEPT
    reason: This location is consistent with PICALM/CALM recruitment to cytosolic 
      membrane interfaces used for clathrin-mediated endocytosis, clathrin-coated 
      vesicle formation, SNARE sorting, and endosomal/synaptic vesicle trafficking.
- term:
    id: GO:0048259
    label: regulation of receptor-mediated endocytosis
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  qualifier: involved_in
  review:
    summary: 'This endocytosis/receptor-internalization term captures the core PICALM role
      in clathrin-mediated internalization and coated-vesicle maturation.'
    action: ACCEPT
    reason: This term aligns with the core PICALM/CALM role as a 
      phosphoinositide-binding clathrin adaptor that organizes clathrin-coated 
      pits/vesicles, controls vesicle curvature and maturation, and sorts endocytic 
      cargo including small R-SNAREs.
- term:
    id: GO:0048268
    label: clathrin coat assembly
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: involved_in
  review:
    summary: 'PICALM is required for orderly clathrin coat and coated-bud formation at the
      plasma membrane.'
    action: ACCEPT
    reason: This term aligns with the core PICALM/CALM role as a 
      phosphoinositide-binding clathrin adaptor that organizes clathrin-coated 
      pits/vesicles, controls vesicle curvature and maturation, and sorts endocytic 
      cargo including small R-SNAREs.
- term:
    id: GO:0072583
    label: clathrin-dependent endocytosis
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: involved_in
  review:
    summary: 'This endocytosis/receptor-internalization term captures the core PICALM role
      in clathrin-mediated internalization and coated-vesicle maturation.'
    action: ACCEPT
    reason: This term aligns with the core PICALM/CALM role as a 
      phosphoinositide-binding clathrin adaptor that organizes clathrin-coated 
      pits/vesicles, controls vesicle curvature and maturation, and sorts endocytic 
      cargo including small R-SNAREs.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:22829078
  qualifier: enables
  review:
    summary: 'The interaction evidence may be real, but generic protein binding is not informative
      for PICALM because specific clathrin, clathrin heavy chain, SNARE, phosphoinositide,
      and cargo-adaptor annotations are available.'
    action: MARK_AS_OVER_ANNOTATED
    reason: This is less informative or less direct than the specific PICALM functions 
      supported by the evidence; prefer clathrin, clathrin heavy chain, SNARE, 
      phosphoinositide, and cargo-trafficking annotations where applicable.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:26496610
  qualifier: enables
  review:
    summary: 'The interaction evidence may be real, but generic protein binding is not informative
      for PICALM because specific clathrin, clathrin heavy chain, SNARE, phosphoinositide,
      and cargo-adaptor annotations are available.'
    action: MARK_AS_OVER_ANNOTATED
    reason: This is less informative or less direct than the specific PICALM functions 
      supported by the evidence; prefer clathrin, clathrin heavy chain, SNARE, 
      phosphoinositide, and cargo-trafficking annotations where applicable.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:35044719
  qualifier: enables
  review:
    summary: 'The interaction evidence may be real, but generic protein binding is not informative
      for PICALM because specific clathrin, clathrin heavy chain, SNARE, phosphoinositide,
      and cargo-adaptor annotations are available.'
    action: MARK_AS_OVER_ANNOTATED
    reason: This is less informative or less direct than the specific PICALM functions 
      supported by the evidence; prefer clathrin, clathrin heavy chain, SNARE, 
      phosphoinositide, and cargo-trafficking annotations where applicable.
- term:
    id: GO:0005794
    label: Golgi apparatus
  evidence_type: EXP
  original_reference_id: PMID:10436022
  qualifier: located_in
  review:
    summary: 'This localization/process is consistent with PICALM acting at cytosolic membrane
      interfaces for clathrin-mediated endocytosis and vesicle trafficking.'
    action: ACCEPT
    reason: This location is consistent with PICALM/CALM recruitment to cytosolic 
      membrane interfaces used for clathrin-mediated endocytosis, clathrin-coated 
      vesicle formation, SNARE sorting, and endosomal/synaptic vesicle trafficking.
- term:
    id: GO:0046579
    label: positive regulation of Ras protein signal transduction
  evidence_type: IMP
  original_reference_id: PMID:26005850
  qualifier: involved_in
  review:
    summary: 'This annotation is supported or plausible for a specific cellular or disease
      context, but it is not the primary PICALM clathrin/SNARE adaptor function.'
    action: KEEP_AS_NON_CORE
    reason: Retain as non-core because the annotation is supported or plausible but 
      represents a cargo-specific, disease-model, endothelial, iron-homeostasis, 
      nuclear/leukemia, or downstream phenotype rather than the primary clathrin/SNARE 
      adaptor function.
- term:
    id: GO:1902991
    label: regulation of amyloid precursor protein catabolic process
  evidence_type: IMP
  original_reference_id: PMID:24577224
  qualifier: involved_in
  review:
    summary: 'The gamma-secretase/APP processing annotation is supported as a cargo-specific
      consequence of CALM-dependent clathrin-mediated endocytosis, not as a separate catalytic
      activity.'
    action: KEEP_AS_NON_CORE
    reason: Retain as non-core because the annotation is supported or plausible but 
      represents a cargo-specific, disease-model, endothelial, iron-homeostasis, 
      nuclear/leukemia, or downstream phenotype rather than the primary clathrin/SNARE 
      adaptor function.
- term:
    id: GO:1902993
    label: positive regulation of amyloid precursor protein catabolic process
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: involved_in
  review:
    summary: 'This annotation is supported or plausible for a specific cellular or disease
      context, but it is not the primary PICALM clathrin/SNARE adaptor function.'
    action: KEEP_AS_NON_CORE
    reason: Retain as non-core because the annotation is supported or plausible but 
      represents a cargo-specific, disease-model, endothelial, iron-homeostasis, 
      nuclear/leukemia, or downstream phenotype rather than the primary clathrin/SNARE 
      adaptor function.
- term:
    id: GO:0048268
    label: clathrin coat assembly
  evidence_type: IDA
  original_reference_id: PMID:16262731
  qualifier: involved_in
  review:
    summary: 'PICALM is required for orderly clathrin coat and coated-bud formation at the
      plasma membrane.'
    action: ACCEPT
    reason: This term aligns with the core PICALM/CALM role as a 
      phosphoinositide-binding clathrin adaptor that organizes clathrin-coated 
      pits/vesicles, controls vesicle curvature and maturation, and sorts endocytic 
      cargo including small R-SNAREs.
- term:
    id: GO:0006879
    label: intracellular iron ion homeostasis
  evidence_type: IMP
  original_reference_id: PMID:22952941
  qualifier: involved_in
  review:
    summary: 'The iron-homeostasis and linked expression/proliferation phenotypes are supported,
      but they arise downstream of transferrin receptor endocytosis rather than defining the
      primary molecular role.'
    action: KEEP_AS_NON_CORE
    reason: Retain as non-core because the annotation is supported or plausible but 
      represents a cargo-specific, disease-model, endothelial, iron-homeostasis, 
      nuclear/leukemia, or downstream phenotype rather than the primary clathrin/SNARE 
      adaptor function.
- term:
    id: GO:0060586
    label: multicellular organismal-level iron ion homeostasis
  evidence_type: IMP
  original_reference_id: PMID:22952941
  qualifier: involved_in
  review:
    summary: 'The iron-homeostasis and linked expression/proliferation phenotypes are supported,
      but they arise downstream of transferrin receptor endocytosis rather than defining the
      primary molecular role.'
    action: KEEP_AS_NON_CORE
    reason: Retain as non-core because the annotation is supported or plausible but 
      represents a cargo-specific, disease-model, endothelial, iron-homeostasis, 
      nuclear/leukemia, or downstream phenotype rather than the primary clathrin/SNARE 
      adaptor function.
- term:
    id: GO:0150093
    label: amyloid-beta clearance by transcytosis
  evidence_type: ISS
  original_reference_id: PMID:26005850
  qualifier: involved_in
  review:
    summary: 'The BBB/endothelial amyloid-beta clearance evidence is strong and Alzheimer-relevant,
      but it is a cargo- and tissue-specific consequence of PICALM-mediated endocytic/transcytotic
      trafficking.'
    action: KEEP_AS_NON_CORE
    reason: Retain as non-core because the annotation is supported or plausible but 
      represents a cargo-specific, disease-model, endothelial, iron-homeostasis, 
      nuclear/leukemia, or downstream phenotype rather than the primary clathrin/SNARE 
      adaptor function.
- term:
    id: GO:0030132
    label: clathrin coat of coated pit
  evidence_type: IDA
  original_reference_id: PMID:10436022
  qualifier: part_of
  review:
    summary: 'PICALM is required for orderly clathrin coat and coated-bud formation at the
      plasma membrane.'
    action: ACCEPT
    reason: This location is consistent with PICALM/CALM recruitment to cytosolic 
      membrane interfaces used for clathrin-mediated endocytosis, clathrin-coated 
      vesicle formation, SNARE sorting, and endosomal/synaptic vesicle trafficking.
- term:
    id: GO:0030132
    label: clathrin coat of coated pit
  evidence_type: IDA
  original_reference_id: PMID:16262731
  qualifier: part_of
  review:
    summary: 'PICALM is required for orderly clathrin coat and coated-bud formation at the
      plasma membrane.'
    action: ACCEPT
    reason: This location is consistent with PICALM/CALM recruitment to cytosolic 
      membrane interfaces used for clathrin-mediated endocytosis, clathrin-coated 
      vesicle formation, SNARE sorting, and endosomal/synaptic vesicle trafficking.
- term:
    id: GO:0031267
    label: small GTPase binding
  evidence_type: IPI
  original_reference_id: PMID:26005850
  qualifier: enables
  review:
    summary: 'The BBB/endothelial amyloid-beta clearance evidence is strong and Alzheimer-relevant,
      but it is a cargo- and tissue-specific consequence of PICALM-mediated endocytic/transcytotic
      trafficking.'
    action: KEEP_AS_NON_CORE
    reason: Retain as non-core because the annotation is supported or plausible but 
      represents a cargo-specific, disease-model, endothelial, iron-homeostasis, 
      nuclear/leukemia, or downstream phenotype rather than the primary clathrin/SNARE 
      adaptor function.
- term:
    id: GO:0050750
    label: low-density lipoprotein particle receptor binding
  evidence_type: IPI
  original_reference_id: PMID:26005850
  qualifier: enables
  review:
    summary: 'The BBB/endothelial amyloid-beta clearance evidence is strong and Alzheimer-relevant,
      but it is a cargo- and tissue-specific consequence of PICALM-mediated endocytic/transcytotic
      trafficking.'
    action: KEEP_AS_NON_CORE
    reason: Retain as non-core because the annotation is supported or plausible but 
      represents a cargo-specific, disease-model, endothelial, iron-homeostasis, 
      nuclear/leukemia, or downstream phenotype rather than the primary clathrin/SNARE 
      adaptor function.
- term:
    id: GO:0000149
    label: SNARE binding
  evidence_type: IDA
  original_reference_id: PMID:22118466
  qualifier: enables
  review:
    summary: 'PICALM directly binds small R-SNAREs such as VAMP2, VAMP3, and VAMP8 and mediates
      their endocytosis.'
    action: ACCEPT
    reason: This term aligns with the core PICALM/CALM role as a 
      phosphoinositide-binding clathrin adaptor that organizes clathrin-coated 
      pits/vesicles, controls vesicle curvature and maturation, and sorts endocytic 
      cargo including small R-SNAREs.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:22118466
  qualifier: enables
  review:
    summary: 'The interaction evidence may be real, but generic protein binding is not informative
      for PICALM because specific clathrin, clathrin heavy chain, SNARE, phosphoinositide,
      and cargo-adaptor annotations are available.'
    action: MARK_AS_OVER_ANNOTATED
    reason: This is less informative or less direct than the specific PICALM functions 
      supported by the evidence; prefer clathrin, clathrin heavy chain, SNARE, 
      phosphoinositide, and cargo-trafficking annotations where applicable.
- term:
    id: GO:0006897
    label: endocytosis
  evidence_type: IDA
  original_reference_id: PMID:22118466
  qualifier: involved_in
  review:
    summary: 'This endocytosis/receptor-internalization term captures the core PICALM role
      in clathrin-mediated internalization and coated-vesicle maturation.'
    action: ACCEPT
    reason: This term aligns with the core PICALM/CALM role as a 
      phosphoinositide-binding clathrin adaptor that organizes clathrin-coated 
      pits/vesicles, controls vesicle curvature and maturation, and sorts endocytic 
      cargo including small R-SNAREs.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:16262731
  qualifier: enables
  review:
    summary: 'The interaction evidence may be real, but generic protein binding is not informative
      for PICALM because specific clathrin, clathrin heavy chain, SNARE, phosphoinositide,
      and cargo-adaptor annotations are available.'
    action: MARK_AS_OVER_ANNOTATED
    reason: This is less informative or less direct than the specific PICALM functions 
      supported by the evidence; prefer clathrin, clathrin heavy chain, SNARE, 
      phosphoinositide, and cargo-trafficking annotations where applicable.
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: IDA
  original_reference_id: PMID:16262731
  qualifier: located_in
  review:
    summary: 'This localization/process is consistent with PICALM acting at cytosolic membrane
      interfaces for clathrin-mediated endocytosis and vesicle trafficking.'
    action: ACCEPT
    reason: This location is consistent with PICALM/CALM recruitment to cytosolic 
      membrane interfaces used for clathrin-mediated endocytosis, clathrin-coated 
      vesicle formation, SNARE sorting, and endosomal/synaptic vesicle trafficking.
- term:
    id: GO:0072583
    label: clathrin-dependent endocytosis
  evidence_type: IMP
  original_reference_id: PMID:26005850
  qualifier: involved_in
  review:
    summary: 'This endocytosis/receptor-internalization term captures the core PICALM role
      in clathrin-mediated internalization and coated-vesicle maturation.'
    action: ACCEPT
    reason: This term aligns with the core PICALM/CALM role as a 
      phosphoinositide-binding clathrin adaptor that organizes clathrin-coated 
      pits/vesicles, controls vesicle curvature and maturation, and sorts endocytic 
      cargo including small R-SNAREs.
- term:
    id: GO:0150093
    label: amyloid-beta clearance by transcytosis
  evidence_type: IGI
  original_reference_id: PMID:26005850
  qualifier: involved_in
  review:
    summary: 'The BBB/endothelial amyloid-beta clearance evidence is strong and Alzheimer-relevant,
      but it is a cargo- and tissue-specific consequence of PICALM-mediated endocytic/transcytotic
      trafficking.'
    action: KEEP_AS_NON_CORE
    reason: Retain as non-core because the annotation is supported or plausible but 
      represents a cargo-specific, disease-model, endothelial, iron-homeostasis, 
      nuclear/leukemia, or downstream phenotype rather than the primary clathrin/SNARE 
      adaptor function.
- term:
    id: GO:0001540
    label: amyloid-beta binding
  evidence_type: IC
  original_reference_id: GO_REF:0000111
  qualifier: enables
  review:
    summary: 'Amyloid-beta binding is not directly established for PICALM in the cited inference;
      the cached BBB study supports PICALM-dependent A-beta/LRP1 trafficking and direct LRP1-tail
      binding rather than direct amyloid-beta binding.'
    action: MARK_AS_OVER_ANNOTATED
    reason: This is less informative or less direct than the specific PICALM functions 
      supported by the evidence; prefer clathrin, clathrin heavy chain, SNARE, 
      phosphoinositide, and cargo-trafficking annotations where applicable.
- term:
    id: GO:0006900
    label: vesicle budding from membrane
  evidence_type: IMP
  original_reference_id: PMID:25898166
  qualifier: involved_in
  review:
    summary: 'This vesicle/coated-pit term is consistent with PICALM acting at clathrin-coated
      pits and clathrin-coated vesicle intermediates.'
    action: ACCEPT
    reason: This term aligns with the core PICALM/CALM role as a 
      phosphoinositide-binding clathrin adaptor that organizes clathrin-coated 
      pits/vesicles, controls vesicle curvature and maturation, and sorts endocytic 
      cargo including small R-SNAREs.
- term:
    id: GO:0048156
    label: tau protein binding
  evidence_type: IPI
  original_reference_id: PMID:23589030
  qualifier: enables
  review:
    summary: 'The tau/neurofibrillary-tangle evidence is Alzheimer-relevant, but it reflects
      pathology-associated localization or binding rather than the main clathrin/SNARE adaptor
      role.'
    action: KEEP_AS_NON_CORE
    reason: Retain as non-core because the annotation is supported or plausible but 
      represents a cargo-specific, disease-model, endothelial, iron-homeostasis, 
      nuclear/leukemia, or downstream phenotype rather than the primary clathrin/SNARE 
      adaptor function.
- term:
    id: GO:0045296
    label: cadherin binding
  evidence_type: HDA
  original_reference_id: PMID:25468996
  qualifier: enables
  review:
    summary: 'The high-throughput cadherin-binding annotation is peripheral to PICALM endocytic
      adaptor biology and is less informative than the supported clathrin/SNARE/phosphoinositide
      binding terms.'
    action: MARK_AS_OVER_ANNOTATED
    reason: This is less informative or less direct than the specific PICALM functions 
      supported by the evidence; prefer clathrin, clathrin heavy chain, SNARE, 
      phosphoinositide, and cargo-trafficking annotations where applicable.
- term:
    id: GO:0031623
    label: receptor internalization
  evidence_type: IMP
  original_reference_id: PMID:25898166
  qualifier: involved_in
  review:
    summary: 'This endocytosis/receptor-internalization term captures the core PICALM role
      in clathrin-mediated internalization and coated-vesicle maturation.'
    action: ACCEPT
    reason: This term aligns with the core PICALM/CALM role as a 
      phosphoinositide-binding clathrin adaptor that organizes clathrin-coated 
      pits/vesicles, controls vesicle curvature and maturation, and sorts endocytic 
      cargo including small R-SNAREs.
- term:
    id: GO:0005546
    label: phosphatidylinositol-4,5-bisphosphate binding
  evidence_type: ISS
  original_reference_id: PMID:25898166
  qualifier: enables
  review:
    summary: 'PICALM/CALM uses its ANTH domain to bind phosphoinositides/PIP2 at clathrin-coated
      membrane sites, anchoring its endocytic adaptor and curvature functions.'
    action: ACCEPT
    reason: This term aligns with the core PICALM/CALM role as a 
      phosphoinositide-binding clathrin adaptor that organizes clathrin-coated 
      pits/vesicles, controls vesicle curvature and maturation, and sorts endocytic 
      cargo including small R-SNAREs.
- term:
    id: GO:0005905
    label: clathrin-coated pit
  evidence_type: IMP
  original_reference_id: PMID:25898166
  qualifier: located_in
  review:
    summary: 'This vesicle/coated-pit term is consistent with PICALM acting at clathrin-coated
      pits and clathrin-coated vesicle intermediates.'
    action: ACCEPT
    reason: This location is consistent with PICALM/CALM recruitment to cytosolic 
      membrane interfaces used for clathrin-mediated endocytosis, clathrin-coated 
      vesicle formation, SNARE sorting, and endosomal/synaptic vesicle trafficking.
- term:
    id: GO:0016020
    label: membrane
  evidence_type: ISS
  original_reference_id: PMID:25898166
  qualifier: located_in
  review:
    summary: 'This localization/process is consistent with PICALM acting at cytosolic membrane
      interfaces for clathrin-mediated endocytosis and vesicle trafficking.'
    action: ACCEPT
    reason: This location is consistent with PICALM/CALM recruitment to cytosolic 
      membrane interfaces used for clathrin-mediated endocytosis, clathrin-coated 
      vesicle formation, SNARE sorting, and endosomal/synaptic vesicle trafficking.
- term:
    id: GO:0030136
    label: clathrin-coated vesicle
  evidence_type: IMP
  original_reference_id: PMID:25898166
  qualifier: located_in
  review:
    summary: 'This vesicle/coated-pit term is consistent with PICALM acting at clathrin-coated
      pits and clathrin-coated vesicle intermediates.'
    action: ACCEPT
    reason: This location is consistent with PICALM/CALM recruitment to cytosolic 
      membrane interfaces used for clathrin-mediated endocytosis, clathrin-coated 
      vesicle formation, SNARE sorting, and endosomal/synaptic vesicle trafficking.
- term:
    id: GO:0045334
    label: clathrin-coated endocytic vesicle
  evidence_type: NAS
  original_reference_id: PMID:25898166
  qualifier: located_in
  review:
    summary: 'This vesicle/coated-pit term is consistent with PICALM acting at clathrin-coated
      pits and clathrin-coated vesicle intermediates.'
    action: ACCEPT
    reason: This location is consistent with PICALM/CALM recruitment to cytosolic 
      membrane interfaces used for clathrin-mediated endocytosis, clathrin-coated 
      vesicle formation, SNARE sorting, and endosomal/synaptic vesicle trafficking.
- term:
    id: GO:0097494
    label: regulation of vesicle size
  evidence_type: IMP
  original_reference_id: PMID:25898166
  qualifier: involved_in
  review:
    summary: 'PICALM regulates clathrin-coated vesicle size, maturation, and membrane curvature
      through its PIP2-bound ANTH/amphipathic-helix module.'
    action: ACCEPT
    reason: This term aligns with the core PICALM/CALM role as a 
      phosphoinositide-binding clathrin adaptor that organizes clathrin-coated 
      pits/vesicles, controls vesicle curvature and maturation, and sorts endocytic 
      cargo including small R-SNAREs.
- term:
    id: GO:0097753
    label: membrane bending
  evidence_type: IMP
  original_reference_id: PMID:25898166
  qualifier: involved_in
  review:
    summary: 'PICALM regulates clathrin-coated vesicle size, maturation, and membrane curvature
      through its PIP2-bound ANTH/amphipathic-helix module.'
    action: ACCEPT
    reason: This term aligns with the core PICALM/CALM role as a 
      phosphoinositide-binding clathrin adaptor that organizes clathrin-coated 
      pits/vesicles, controls vesicle curvature and maturation, and sorts endocytic 
      cargo including small R-SNAREs.
- term:
    id: GO:0007611
    label: learning or memory
  evidence_type: ISS
  original_reference_id: PMID:26005850
  qualifier: involved_in
  review:
    summary: 'This annotation is supported or plausible for a specific cellular or disease
      context, but it is not the primary PICALM clathrin/SNARE adaptor function.'
    action: KEEP_AS_NON_CORE
    reason: Retain as non-core because the annotation is supported or plausible but 
      represents a cargo-specific, disease-model, endothelial, iron-homeostasis, 
      nuclear/leukemia, or downstream phenotype rather than the primary clathrin/SNARE 
      adaptor function.
- term:
    id: GO:1902003
    label: regulation of amyloid-beta formation
  evidence_type: ISS
  original_reference_id: PMID:26005850
  qualifier: involved_in
  negated: true
  review:
    summary: 'This is a NOT annotation for regulation of amyloid-beta formation; it should
      be retained because the cited disease-model evidence supports amyloid-beta clearance/transcytosis
      rather than amyloid-beta production by PICALM.'
    action: ACCEPT
    reason: The NOT annotation is consistent with evidence that the referenced study 
      separated PICALM-dependent amyloid-beta clearance from amyloid-beta 
      production/formation.
- term:
    id: GO:1903077
    label: negative regulation of protein localization to plasma membrane
  evidence_type: IMP
  original_reference_id: PMID:21221849
  qualifier: involved_in
  review:
    summary: 'The GluR2/postsynaptic trafficking evidence is plausible but cargo-specific
      and not the main PICALM clathrin coat/SNARE sorting function.'
    action: KEEP_AS_NON_CORE
    reason: Retain as non-core because the annotation is supported or plausible but 
      represents a cargo-specific, disease-model, endothelial, iron-homeostasis, 
      nuclear/leukemia, or downstream phenotype rather than the primary clathrin/SNARE 
      adaptor function.
- term:
    id: GO:2000009
    label: negative regulation of protein localization to cell surface
  evidence_type: IMP
  original_reference_id: PMID:21221849
  qualifier: involved_in
  review:
    summary: 'The GluR2/postsynaptic trafficking evidence is plausible but cargo-specific
      and not the main PICALM clathrin coat/SNARE sorting function.'
    action: KEEP_AS_NON_CORE
    reason: Retain as non-core because the annotation is supported or plausible but 
      represents a cargo-specific, disease-model, endothelial, iron-homeostasis, 
      nuclear/leukemia, or downstream phenotype rather than the primary clathrin/SNARE 
      adaptor function.
- term:
    id: GO:0005769
    label: early endosome
  evidence_type: IDA
  original_reference_id: PMID:26005850
  qualifier: located_in
  review:
    summary: 'This endosomal/cargo-trafficking term is consistent with PICALM-mediated sorting
      of endocytic cargo between plasma membrane and endosomal compartments.'
    action: ACCEPT
    reason: This location is consistent with PICALM/CALM recruitment to cytosolic 
      membrane interfaces used for clathrin-mediated endocytosis, clathrin-coated 
      vesicle formation, SNARE sorting, and endosomal/synaptic vesicle trafficking.
- term:
    id: GO:0070381
    label: endosome to plasma membrane transport vesicle
  evidence_type: IDA
  original_reference_id: PMID:26005850
  qualifier: located_in
  review:
    summary: 'This endosomal/cargo-trafficking term is consistent with PICALM-mediated sorting
      of endocytic cargo between plasma membrane and endosomal compartments.'
    action: ACCEPT
    reason: This location is consistent with PICALM/CALM recruitment to cytosolic 
      membrane interfaces used for clathrin-mediated endocytosis, clathrin-coated 
      vesicle formation, SNARE sorting, and endosomal/synaptic vesicle trafficking.
- term:
    id: GO:0009986
    label: cell surface
  evidence_type: IDA
  original_reference_id: PMID:26005850
  qualifier: located_in
  review:
    summary: 'This localization/process is consistent with PICALM acting at cytosolic membrane
      interfaces for clathrin-mediated endocytosis and vesicle trafficking.'
    action: ACCEPT
    reason: This location is consistent with PICALM/CALM recruitment to cytosolic 
      membrane interfaces used for clathrin-mediated endocytosis, clathrin-coated 
      vesicle formation, SNARE sorting, and endosomal/synaptic vesicle trafficking.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8867613
  qualifier: located_in
  review:
    summary: 'This localization/process is consistent with PICALM acting at cytosolic membrane
      interfaces for clathrin-mediated endocytosis and vesicle trafficking.'
    action: ACCEPT
    reason: This location is consistent with PICALM/CALM recruitment to cytosolic 
      membrane interfaces used for clathrin-mediated endocytosis, clathrin-coated 
      vesicle formation, SNARE sorting, and endosomal/synaptic vesicle trafficking.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8867754
  qualifier: located_in
  review:
    summary: 'This localization/process is consistent with PICALM acting at cytosolic membrane
      interfaces for clathrin-mediated endocytosis and vesicle trafficking.'
    action: ACCEPT
    reason: This location is consistent with PICALM/CALM recruitment to cytosolic 
      membrane interfaces used for clathrin-mediated endocytosis, clathrin-coated 
      vesicle formation, SNARE sorting, and endosomal/synaptic vesicle trafficking.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8867756
  qualifier: located_in
  review:
    summary: 'This localization/process is consistent with PICALM acting at cytosolic membrane
      interfaces for clathrin-mediated endocytosis and vesicle trafficking.'
    action: ACCEPT
    reason: This location is consistent with PICALM/CALM recruitment to cytosolic 
      membrane interfaces used for clathrin-mediated endocytosis, clathrin-coated 
      vesicle formation, SNARE sorting, and endosomal/synaptic vesicle trafficking.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8868071
  qualifier: located_in
  review:
    summary: 'This localization/process is consistent with PICALM acting at cytosolic membrane
      interfaces for clathrin-mediated endocytosis and vesicle trafficking.'
    action: ACCEPT
    reason: This location is consistent with PICALM/CALM recruitment to cytosolic 
      membrane interfaces used for clathrin-mediated endocytosis, clathrin-coated 
      vesicle formation, SNARE sorting, and endosomal/synaptic vesicle trafficking.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8868072
  qualifier: located_in
  review:
    summary: 'This localization/process is consistent with PICALM acting at cytosolic membrane
      interfaces for clathrin-mediated endocytosis and vesicle trafficking.'
    action: ACCEPT
    reason: This location is consistent with PICALM/CALM recruitment to cytosolic 
      membrane interfaces used for clathrin-mediated endocytosis, clathrin-coated 
      vesicle formation, SNARE sorting, and endosomal/synaptic vesicle trafficking.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8868230
  qualifier: located_in
  review:
    summary: 'This localization/process is consistent with PICALM acting at cytosolic membrane
      interfaces for clathrin-mediated endocytosis and vesicle trafficking.'
    action: ACCEPT
    reason: This location is consistent with PICALM/CALM recruitment to cytosolic 
      membrane interfaces used for clathrin-mediated endocytosis, clathrin-coated 
      vesicle formation, SNARE sorting, and endosomal/synaptic vesicle trafficking.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8868236
  qualifier: located_in
  review:
    summary: 'This localization/process is consistent with PICALM acting at cytosolic membrane
      interfaces for clathrin-mediated endocytosis and vesicle trafficking.'
    action: ACCEPT
    reason: This location is consistent with PICALM/CALM recruitment to cytosolic 
      membrane interfaces used for clathrin-mediated endocytosis, clathrin-coated 
      vesicle formation, SNARE sorting, and endosomal/synaptic vesicle trafficking.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8868648
  qualifier: located_in
  review:
    summary: 'This localization/process is consistent with PICALM acting at cytosolic membrane
      interfaces for clathrin-mediated endocytosis and vesicle trafficking.'
    action: ACCEPT
    reason: This location is consistent with PICALM/CALM recruitment to cytosolic 
      membrane interfaces used for clathrin-mediated endocytosis, clathrin-coated 
      vesicle formation, SNARE sorting, and endosomal/synaptic vesicle trafficking.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8868651
  qualifier: located_in
  review:
    summary: 'This localization/process is consistent with PICALM acting at cytosolic membrane
      interfaces for clathrin-mediated endocytosis and vesicle trafficking.'
    action: ACCEPT
    reason: This location is consistent with PICALM/CALM recruitment to cytosolic 
      membrane interfaces used for clathrin-mediated endocytosis, clathrin-coated 
      vesicle formation, SNARE sorting, and endosomal/synaptic vesicle trafficking.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8868658
  qualifier: located_in
  review:
    summary: 'This localization/process is consistent with PICALM acting at cytosolic membrane
      interfaces for clathrin-mediated endocytosis and vesicle trafficking.'
    action: ACCEPT
    reason: This location is consistent with PICALM/CALM recruitment to cytosolic 
      membrane interfaces used for clathrin-mediated endocytosis, clathrin-coated 
      vesicle formation, SNARE sorting, and endosomal/synaptic vesicle trafficking.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8868659
  qualifier: located_in
  review:
    summary: 'This localization/process is consistent with PICALM acting at cytosolic membrane
      interfaces for clathrin-mediated endocytosis and vesicle trafficking.'
    action: ACCEPT
    reason: This location is consistent with PICALM/CALM recruitment to cytosolic 
      membrane interfaces used for clathrin-mediated endocytosis, clathrin-coated 
      vesicle formation, SNARE sorting, and endosomal/synaptic vesicle trafficking.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8868660
  qualifier: located_in
  review:
    summary: 'This localization/process is consistent with PICALM acting at cytosolic membrane
      interfaces for clathrin-mediated endocytosis and vesicle trafficking.'
    action: ACCEPT
    reason: This location is consistent with PICALM/CALM recruitment to cytosolic 
      membrane interfaces used for clathrin-mediated endocytosis, clathrin-coated 
      vesicle formation, SNARE sorting, and endosomal/synaptic vesicle trafficking.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8868661
  qualifier: located_in
  review:
    summary: 'This localization/process is consistent with PICALM acting at cytosolic membrane
      interfaces for clathrin-mediated endocytosis and vesicle trafficking.'
    action: ACCEPT
    reason: This location is consistent with PICALM/CALM recruitment to cytosolic 
      membrane interfaces used for clathrin-mediated endocytosis, clathrin-coated 
      vesicle formation, SNARE sorting, and endosomal/synaptic vesicle trafficking.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8869438
  qualifier: located_in
  review:
    summary: 'This localization/process is consistent with PICALM acting at cytosolic membrane
      interfaces for clathrin-mediated endocytosis and vesicle trafficking.'
    action: ACCEPT
    reason: This location is consistent with PICALM/CALM recruitment to cytosolic 
      membrane interfaces used for clathrin-mediated endocytosis, clathrin-coated 
      vesicle formation, SNARE sorting, and endosomal/synaptic vesicle trafficking.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8871193
  qualifier: located_in
  review:
    summary: 'This localization/process is consistent with PICALM acting at cytosolic membrane
      interfaces for clathrin-mediated endocytosis and vesicle trafficking.'
    action: ACCEPT
    reason: This location is consistent with PICALM/CALM recruitment to cytosolic 
      membrane interfaces used for clathrin-mediated endocytosis, clathrin-coated 
      vesicle formation, SNARE sorting, and endosomal/synaptic vesicle trafficking.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8871194
  qualifier: located_in
  review:
    summary: 'This localization/process is consistent with PICALM acting at cytosolic membrane
      interfaces for clathrin-mediated endocytosis and vesicle trafficking.'
    action: ACCEPT
    reason: This location is consistent with PICALM/CALM recruitment to cytosolic 
      membrane interfaces used for clathrin-mediated endocytosis, clathrin-coated 
      vesicle formation, SNARE sorting, and endosomal/synaptic vesicle trafficking.
- term:
    id: GO:0016020
    label: membrane
  evidence_type: HDA
  original_reference_id: PMID:19946888
  qualifier: located_in
  review:
    summary: 'This localization/process is consistent with PICALM acting at cytosolic membrane
      interfaces for clathrin-mediated endocytosis and vesicle trafficking.'
    action: ACCEPT
    reason: This location is consistent with PICALM/CALM recruitment to cytosolic 
      membrane interfaces used for clathrin-mediated endocytosis, clathrin-coated 
      vesicle formation, SNARE sorting, and endosomal/synaptic vesicle trafficking.
- term:
    id: GO:0016188
    label: synaptic vesicle maturation
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: involved_in
  review:
    summary: 'This synaptic-vesicle/presynaptic term is consistent with PICALM/AP180-family
      SNARE sorting and synaptic vesicle trafficking biology.'
    action: ACCEPT
    reason: This term aligns with the core PICALM/CALM role as a 
      phosphoinositide-binding clathrin adaptor that organizes clathrin-coated 
      pits/vesicles, controls vesicle curvature and maturation, and sorts endocytic 
      cargo including small R-SNAREs.
- term:
    id: GO:0031982
    label: vesicle
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: located_in
  review:
    summary: 'This vesicle/coated-pit term is consistent with PICALM acting at clathrin-coated
      pits and clathrin-coated vesicle intermediates.'
    action: ACCEPT
    reason: This location is consistent with PICALM/CALM recruitment to cytosolic 
      membrane interfaces used for clathrin-mediated endocytosis, clathrin-coated 
      vesicle formation, SNARE sorting, and endosomal/synaptic vesicle trafficking.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:23382074
  qualifier: enables
  review:
    summary: 'The interaction evidence may be real, but generic protein binding is not informative
      for PICALM because specific clathrin, clathrin heavy chain, SNARE, phosphoinositide,
      and cargo-adaptor annotations are available.'
    action: MARK_AS_OVER_ANNOTATED
    reason: This is less informative or less direct than the specific PICALM functions 
      supported by the evidence; prefer clathrin, clathrin heavy chain, SNARE, 
      phosphoinositide, and cargo-trafficking annotations where applicable.
- term:
    id: GO:1902004
    label: positive regulation of amyloid-beta formation
  evidence_type: IMP
  original_reference_id: PMID:24577224
  qualifier: involved_in
  review:
    summary: 'The gamma-secretase/APP processing annotation is supported as a cargo-specific
      consequence of CALM-dependent clathrin-mediated endocytosis, not as a separate catalytic
      activity.'
    action: KEEP_AS_NON_CORE
    reason: Retain as non-core because the annotation is supported or plausible but 
      represents a cargo-specific, disease-model, endothelial, iron-homeostasis, 
      nuclear/leukemia, or downstream phenotype rather than the primary clathrin/SNARE 
      adaptor function.
- term:
    id: GO:0010629
    label: negative regulation of gene expression
  evidence_type: IMP
  original_reference_id: PMID:22952941
  qualifier: involved_in
  review:
    summary: 'The iron-homeostasis and linked expression/proliferation phenotypes are supported,
      but they arise downstream of transferrin receptor endocytosis rather than defining the
      primary molecular role.'
    action: KEEP_AS_NON_CORE
    reason: Retain as non-core because the annotation is supported or plausible but 
      represents a cargo-specific, disease-model, endothelial, iron-homeostasis, 
      nuclear/leukemia, or downstream phenotype rather than the primary clathrin/SNARE 
      adaptor function.
- term:
    id: GO:0072583
    label: clathrin-dependent endocytosis
  evidence_type: IMP
  original_reference_id: PMID:22952941
  qualifier: involved_in
  review:
    summary: 'This endocytosis/receptor-internalization term captures the core PICALM role
      in clathrin-mediated internalization and coated-vesicle maturation.'
    action: ACCEPT
    reason: This term aligns with the core PICALM/CALM role as a 
      phosphoinositide-binding clathrin adaptor that organizes clathrin-coated 
      pits/vesicles, controls vesicle curvature and maturation, and sorts endocytic 
      cargo including small R-SNAREs.
- term:
    id: GO:0035459
    label: vesicle cargo loading
  evidence_type: IMP
  original_reference_id: PMID:24577224
  qualifier: involved_in
  review:
    summary: 'This endosomal/cargo-trafficking term is consistent with PICALM-mediated sorting
      of endocytic cargo between plasma membrane and endosomal compartments.'
    action: ACCEPT
    reason: This term aligns with the core PICALM/CALM role as a 
      phosphoinositide-binding clathrin adaptor that organizes clathrin-coated 
      pits/vesicles, controls vesicle curvature and maturation, and sorts endocytic 
      cargo including small R-SNAREs.
- term:
    id: GO:0043025
    label: neuronal cell body
  evidence_type: IDA
  original_reference_id: PMID:23589030
  qualifier: located_in
  review:
    summary: 'The tau/neurofibrillary-tangle evidence is Alzheimer-relevant, but it reflects
      pathology-associated localization or binding rather than the main clathrin/SNARE adaptor
      role.'
    action: KEEP_AS_NON_CORE
    reason: Retain as non-core because the annotation is supported or plausible but 
      represents a cargo-specific, disease-model, endothelial, iron-homeostasis, 
      nuclear/leukemia, or downstream phenotype rather than the primary clathrin/SNARE 
      adaptor function.
- term:
    id: GO:0072583
    label: clathrin-dependent endocytosis
  evidence_type: IMP
  original_reference_id: PMID:24577224
  qualifier: involved_in
  review:
    summary: 'This endocytosis/receptor-internalization term captures the core PICALM role
      in clathrin-mediated internalization and coated-vesicle maturation.'
    action: ACCEPT
    reason: This term aligns with the core PICALM/CALM role as a 
      phosphoinositide-binding clathrin adaptor that organizes clathrin-coated 
      pits/vesicles, controls vesicle curvature and maturation, and sorts endocytic 
      cargo including small R-SNAREs.
- term:
    id: GO:0097418
    label: neurofibrillary tangle
  evidence_type: IMP
  original_reference_id: PMID:23589030
  qualifier: located_in
  review:
    summary: 'The tau/neurofibrillary-tangle evidence is Alzheimer-relevant, but it reflects
      pathology-associated localization or binding rather than the main clathrin/SNARE adaptor
      role.'
    action: KEEP_AS_NON_CORE
    reason: Retain as non-core because the annotation is supported or plausible but 
      represents a cargo-specific, disease-model, endothelial, iron-homeostasis, 
      nuclear/leukemia, or downstream phenotype rather than the primary clathrin/SNARE 
      adaptor function.
- term:
    id: GO:0031623
    label: receptor internalization
  evidence_type: IMP
  original_reference_id: PMID:14985334
  qualifier: involved_in
  review:
    summary: 'This endocytosis/receptor-internalization term captures the core PICALM role
      in clathrin-mediated internalization and coated-vesicle maturation.'
    action: ACCEPT
    reason: This term aligns with the core PICALM/CALM role as a 
      phosphoinositide-binding clathrin adaptor that organizes clathrin-coated 
      pits/vesicles, controls vesicle curvature and maturation, and sorts endocytic 
      cargo including small R-SNAREs.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:16491119
  qualifier: enables
  review:
    summary: 'The interaction evidence may be real, but generic protein binding is not informative
      for PICALM because specific clathrin, clathrin heavy chain, SNARE, phosphoinositide,
      and cargo-adaptor annotations are available.'
    action: MARK_AS_OVER_ANNOTATED
    reason: This is less informative or less direct than the specific PICALM functions 
      supported by the evidence; prefer clathrin, clathrin heavy chain, SNARE, 
      phosphoinositide, and cargo-trafficking annotations where applicable.
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: IDA
  original_reference_id: PMID:16491119
  qualifier: located_in
  review:
    summary: 'Nuclear localization and transcriptional effects are context-specific, mainly
      from nuclear shuttling or leukemia-fusion/interactor biology, and are not the principal
      PICALM function.'
    action: KEEP_AS_NON_CORE
    reason: Retain as non-core because the annotation is supported or plausible but 
      represents a cargo-specific, disease-model, endothelial, iron-homeostasis, 
      nuclear/leukemia, or downstream phenotype rather than the primary clathrin/SNARE 
      adaptor function.
- term:
    id: GO:0045893
    label: positive regulation of DNA-templated transcription
  evidence_type: IDA
  original_reference_id: PMID:11425879
  qualifier: involved_in
  review:
    summary: 'Nuclear localization and transcriptional effects are context-specific, mainly
      from nuclear shuttling or leukemia-fusion/interactor biology, and are not the principal
      PICALM function.'
    action: KEEP_AS_NON_CORE
    reason: Retain as non-core because the annotation is supported or plausible but 
      represents a cargo-specific, disease-model, endothelial, iron-homeostasis, 
      nuclear/leukemia, or downstream phenotype rather than the primary clathrin/SNARE 
      adaptor function.
- term:
    id: GO:0032050
    label: clathrin heavy chain binding
  evidence_type: IDA
  original_reference_id: PMID:10436022
  qualifier: enables
  review:
    summary: 'Direct clathrin/clathrin-heavy-chain binding is central to PICALM recruitment
      and clathrin-coated pit/vesicle assembly.'
    action: ACCEPT
    reason: This term aligns with the core PICALM/CALM role as a 
      phosphoinositide-binding clathrin adaptor that organizes clathrin-coated 
      pits/vesicles, controls vesicle curvature and maturation, and sorts endocytic 
      cargo including small R-SNAREs.
- term:
    id: GO:0032880
    label: regulation of protein localization
  evidence_type: IDA
  original_reference_id: PMID:10436022
  qualifier: involved_in
  review:
    summary: 'This localization/process is consistent with PICALM acting at cytosolic membrane
      interfaces for clathrin-mediated endocytosis and vesicle trafficking.'
    action: ACCEPT
    reason: This term aligns with the core PICALM/CALM role as a 
      phosphoinositide-binding clathrin adaptor that organizes clathrin-coated 
      pits/vesicles, controls vesicle curvature and maturation, and sorts endocytic 
      cargo including small R-SNAREs.
- term:
    id: GO:0048261
    label: negative regulation of receptor-mediated endocytosis
  evidence_type: IDA
  original_reference_id: PMID:10436022
  qualifier: involved_in
  review:
    summary: 'The negative regulation term reflects dominant-negative overexpression effects
      on receptor endocytosis, whereas loss-of-function and rescue studies support a normal
      positive/core role in clathrin-mediated internalization.'
    action: MARK_AS_OVER_ANNOTATED
    reason: The annotation is not simply wrong, but it over-emphasizes an overexpression
      phenotype and can misrepresent normal PICALM biology; receptor-mediated 
      endocytosis and clathrin-dependent endocytosis capture the core process better.
- term:
    id: GO:0016197
    label: endosomal transport
  evidence_type: IMP
  original_reference_id: PMID:16262731
  qualifier: involved_in
  review:
    summary: 'This endosomal/cargo-trafficking term is consistent with PICALM-mediated sorting
      of endocytic cargo between plasma membrane and endosomal compartments.'
    action: ACCEPT
    reason: This term aligns with the core PICALM/CALM role as a 
      phosphoinositide-binding clathrin adaptor that organizes clathrin-coated 
      pits/vesicles, controls vesicle curvature and maturation, and sorts endocytic 
      cargo including small R-SNAREs.
- term:
    id: GO:0030276
    label: clathrin binding
  evidence_type: IDA
  original_reference_id: PMID:16262731
  qualifier: enables
  review:
    summary: 'Direct clathrin/clathrin-heavy-chain binding is central to PICALM recruitment
      and clathrin-coated pit/vesicle assembly.'
    action: ACCEPT
    reason: This term aligns with the core PICALM/CALM role as a 
      phosphoinositide-binding clathrin adaptor that organizes clathrin-coated 
      pits/vesicles, controls vesicle curvature and maturation, and sorts endocytic 
      cargo including small R-SNAREs.
- term:
    id: GO:0048268
    label: clathrin coat assembly
  evidence_type: IMP
  original_reference_id: PMID:16262731
  qualifier: involved_in
  review:
    summary: 'PICALM is required for orderly clathrin coat and coated-bud formation at the
      plasma membrane.'
    action: ACCEPT
    reason: This term aligns with the core PICALM/CALM role as a 
      phosphoinositide-binding clathrin adaptor that organizes clathrin-coated 
      pits/vesicles, controls vesicle curvature and maturation, and sorts endocytic 
      cargo including small R-SNAREs.
- term:
    id: GO:0030100
    label: regulation of endocytosis
  evidence_type: IMP
  original_reference_id: PMID:18182011
  qualifier: involved_in
  review:
    summary: 'This endocytosis/receptor-internalization term captures the core PICALM role
      in clathrin-mediated internalization and coated-vesicle maturation.'
    action: ACCEPT
    reason: This term aligns with the core PICALM/CALM role as a 
      phosphoinositide-binding clathrin adaptor that organizes clathrin-coated 
      pits/vesicles, controls vesicle curvature and maturation, and sorts endocytic 
      cargo including small R-SNAREs.
- term:
    id: GO:0042734
    label: presynaptic membrane
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: located_in
  review:
    summary: 'This synaptic-vesicle/presynaptic term is consistent with PICALM/AP180-family
      SNARE sorting and synaptic vesicle trafficking biology.'
    action: ACCEPT
    reason: This location is consistent with PICALM/CALM recruitment to cytosolic 
      membrane interfaces used for clathrin-mediated endocytosis, clathrin-coated 
      vesicle formation, SNARE sorting, and endosomal/synaptic vesicle trafficking.
- term:
    id: GO:0045211
    label: postsynaptic membrane
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: located_in
  review:
    summary: 'The GluR2/postsynaptic trafficking evidence is plausible but cargo-specific
      and not the main PICALM clathrin coat/SNARE sorting function.'
    action: KEEP_AS_NON_CORE
    reason: Retain as non-core because the annotation is supported or plausible but 
      represents a cargo-specific, disease-model, endothelial, iron-homeostasis, 
      nuclear/leukemia, or downstream phenotype rather than the primary clathrin/SNARE 
      adaptor function.
- term:
    id: GO:0048471
    label: perinuclear region of cytoplasm
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: colocalizes_with
  review:
    summary: 'This annotation is supported or plausible for a specific cellular or disease
      context, but it is not the primary PICALM clathrin/SNARE adaptor function.'
    action: KEEP_AS_NON_CORE
    reason: Retain as non-core because the annotation is supported or plausible but 
      represents a cargo-specific, disease-model, endothelial, iron-homeostasis, 
      nuclear/leukemia, or downstream phenotype rather than the primary clathrin/SNARE 
      adaptor function.
- term:
    id: GO:0005545
    label: 1-phosphatidylinositol binding
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: enables
  review:
    summary: 'PICALM/CALM uses its ANTH domain to bind phosphoinositides/PIP2 at clathrin-coated
      membrane sites, anchoring its endocytic adaptor and curvature functions.'
    action: ACCEPT
    reason: This term aligns with the core PICALM/CALM role as a 
      phosphoinositide-binding clathrin adaptor that organizes clathrin-coated 
      pits/vesicles, controls vesicle curvature and maturation, and sorts endocytic 
      cargo including small R-SNAREs.
- term:
    id: GO:0005905
    label: clathrin-coated pit
  evidence_type: IDA
  original_reference_id: PMID:10436022
  qualifier: located_in
  review:
    summary: 'This vesicle/coated-pit term is consistent with PICALM acting at clathrin-coated
      pits and clathrin-coated vesicle intermediates.'
    action: ACCEPT
    reason: This location is consistent with PICALM/CALM recruitment to cytosolic 
      membrane interfaces used for clathrin-mediated endocytosis, clathrin-coated 
      vesicle formation, SNARE sorting, and endosomal/synaptic vesicle trafficking.
- term:
    id: GO:0006898
    label: receptor-mediated endocytosis
  evidence_type: IDA
  original_reference_id: PMID:10436022
  qualifier: involved_in
  review:
    summary: 'This endocytosis/receptor-internalization term captures the core PICALM role
      in clathrin-mediated internalization and coated-vesicle maturation.'
    action: ACCEPT
    reason: This term aligns with the core PICALM/CALM role as a 
      phosphoinositide-binding clathrin adaptor that organizes clathrin-coated 
      pits/vesicles, controls vesicle curvature and maturation, and sorts endocytic 
      cargo including small R-SNAREs.
- term:
    id: GO:0030276
    label: clathrin binding
  evidence_type: IDA
  original_reference_id: PMID:10436022
  qualifier: enables
  review:
    summary: 'Direct clathrin/clathrin-heavy-chain binding is central to PICALM recruitment
      and clathrin-coated pit/vesicle assembly.'
    action: ACCEPT
    reason: This term aligns with the core PICALM/CALM role as a 
      phosphoinositide-binding clathrin adaptor that organizes clathrin-coated 
      pits/vesicles, controls vesicle curvature and maturation, and sorts endocytic 
      cargo including small R-SNAREs.
- term:
    id: GO:0016192
    label: vesicle-mediated transport
  evidence_type: TAS
  original_reference_id: PMID:8643484
  qualifier: involved_in
  review:
    summary: 'This vesicle/coated-pit term is consistent with PICALM acting at clathrin-coated
      pits and clathrin-coated vesicle intermediates.'
    action: ACCEPT
    reason: This term aligns with the core PICALM/CALM role as a 
      phosphoinositide-binding clathrin adaptor that organizes clathrin-coated 
      pits/vesicles, controls vesicle curvature and maturation, and sorts endocytic 
      cargo including small R-SNAREs.
- term:
    id: GO:0065003
    label: protein-containing complex assembly
  evidence_type: TAS
  original_reference_id: PMID:8643484
  qualifier: involved_in
  review:
    summary: 'The generic protein-containing complex assembly annotation is too broad for
      PICALM; the supported complex-assembly role is clathrin coat assembly.'
    action: MODIFY
    reason: The source publication identifies CALM as a clathrin assembly protein family
      member, and later direct evidence supports clathrin coat formation; use the 
      specific clathrin coat assembly term instead of a generic complex-assembly term.
    proposed_replacement_terms:
    - id: GO:0048268
      label: clathrin coat assembly
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: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:0000111
  title: Gene Ontology annotations Inferred by Curator (IC) using at least one Inferred 
    by Sequence Similarity (ISS) annotation to support the inference
  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:10436022
  title: 'Clathrin assembly lymphoid myeloid leukemia (CALM) protein: localization in endocytic-coated
    pits, interactions with clathrin, and the impact of overexpression on clathrin-mediated
    traffic.'
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Full text cached; direct evidence for clathrin heavy chain binding, 
      coated-pit localization, Golgi colocalization, and effects on receptor 
      endocytosis.
- id: PMID:11425879
  title: Nucleocytoplasmic shuttling of endocytic proteins.
  findings: []
- id: PMID:14985334
  title: Analysis of clathrin-mediated endocytosis of epidermal growth factor receptor 
    by RNA interference.
  findings: []
- id: PMID:16262731
  title: Effect of clathrin assembly lymphoid myeloid leukemia protein depletion on 
    clathrin coat formation.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Abstract cached; direct depletion evidence supports CALM roles in 
      AP2/clathrin association and orderly clathrin-coated bud formation.
- id: PMID:16491119
  title: The novel CALM interactor CATS influences the subcellular localization of the 
    leukemogenic fusion protein CALM/AF10.
  findings: []
- id: PMID:18182011
  title: Evidence for CALM in directing VAMP2 trafficking.
  findings: []
- id: PMID:19946888
  title: Defining the membrane proteome of NK cells.
  findings: []
- id: PMID:21221849
  title: CALM, a clathrin assembly protein, influences cell surface GluR2 abundance.
  findings: []
- id: PMID:22118466
  title: The molecular basis for the endocytosis of small R-SNAREs by the clathrin 
    adaptor CALM.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Full text cached; direct biochemical, structural, and cell-biological 
      evidence for CALM/PICALM binding and endocytosis of small R-SNAREs.
- id: PMID:22829078
  title: FHL2 interacts with CALM and is highly expressed in acute erythroid leukemia.
  findings: []
- id: PMID:22952941
  title: The PICALM protein plays a key role in iron homeostasis and cell proliferation.
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: Full text cached; supports transferrin receptor internalization and 
      iron-homeostasis phenotypes downstream of PICALM endocytic function.
- id: PMID:23382074
  title: A high-confidence interaction map identifies SIRT1 as a mediator of acetylation
    of USP22 and the SAGA coactivator complex.
  findings: []
- id: PMID:23589030
  title: Clathrin adaptor CALM/PICALM is associated with neurofibrillary tangles and is 
    cleaved in Alzheimer's brains.
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: Abstract cached; supports Alzheimer tau-pathology association and 
      PHF-tau co-immunoprecipitation as non-core disease context.
- id: PMID:24577224
  title: Decreased CALM expression reduces Aβ42 to total Aβ ratio through 
    clathrin-mediated endocytosis of γ-secretase.
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: Abstract cached; supports gamma-secretase trafficking and amyloid-beta
      species effects as cargo-specific consequences of CALM-dependent endocytosis.
- id: PMID:25468996
  title: E-cadherin interactome complexity and robustness resolved by quantitative 
    proteomics.
  findings: []
- id: PMID:25898166
  title: CALM regulates clathrin-coated vesicle size and maturation by directly sensing 
    and driving membrane curvature.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Full text cached; direct evidence that CALM controls clathrin-coated 
      vesicle size, maturation, membrane curvature, and endocytic uptake.
- id: PMID:26005850
  title: Central role for PICALM in amyloid-β blood-brain barrier transcytosis and 
    clearance.
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: Full text cached; strong Alzheimer-relevant evidence for endothelial 
      amyloid-beta/LRP1 transcytosis and clearance, retained as non-core disease/cargo 
      context.
- id: PMID:26496610
  title: A human interactome in three quantitative dimensions organized by 
    stoichiometries and abundances.
  findings: []
- id: PMID:35044719
  title: Proteome-scale mapping of binding sites in the unstructured regions of the 
    human proteome.
  findings: []
- id: PMID:8643484
  title: The t(10;11)(p13;q14) in the U937 cell line results in the fusion of the AF10 
    gene and CALM, encoding a new member of the AP-3 clathrin assembly protein family.
  findings: []
- id: Reactome:R-HSA-8867613
  title: PICALM binds R-SNAREs
  findings: []
- id: Reactome:R-HSA-8867754
  title: F- and N- BAR domain proteins bind the clathrin-coated pit
  findings: []
- id: Reactome:R-HSA-8867756
  title: CLASP proteins and cargo are recruited to the nascent clathrin-coated pit
  findings: []
- id: Reactome:R-HSA-8868071
  title: Clathrin recruits PIK3C2A
  findings: []
- id: Reactome:R-HSA-8868072
  title: Clathrin-associated PIK3C2A phosphorylates PI(4)P to PI(3,4)P2
  findings: []
- id: Reactome:R-HSA-8868230
  title: SNX9 recruits components of the actin polymerizing machinery
  findings: []
- id: Reactome:R-HSA-8868236
  title: BAR domain proteins recruit dynamin
  findings: []
- id: Reactome:R-HSA-8868648
  title: SYNJ hydrolyze PI(4,5)P2 to PI(4)P
  findings: []
- id: Reactome:R-HSA-8868651
  title: Endophilins recruit synaptojanins to the clathrin-coated pit
  findings: []
- id: Reactome:R-HSA-8868658
  title: HSPA8-mediated ATP hydrolysis promotes vesicle uncoating
  findings: []
- id: Reactome:R-HSA-8868659
  title: Clathrin recruits auxilins to the clathrin-coated vesicle
  findings: []
- id: Reactome:R-HSA-8868660
  title: Auxilin recruits HSPA8:ATP to the clathrin-coated vesicle
  findings: []
- id: Reactome:R-HSA-8868661
  title: Dynamin-mediated GTP hydrolysis promotes vesicle scission
  findings: []
- id: Reactome:R-HSA-8869438
  title: Dissociation of clathrin-associated proteins
  findings: []
- id: Reactome:R-HSA-8871193
  title: Dissociation of AAK1 and dephosphorylation of AP-2 mu2
  findings: []
- id: Reactome:R-HSA-8871194
  title: RAB5 and GAPVD1 bind AP-2
  findings: []
core_functions:
- molecular_function:
    id: GO:0005546
    label: phosphatidylinositol-4,5-bisphosphate binding
  description: PICALM binds PIP2/phosphoinositide-rich cytosolic membrane surfaces 
    through its ANTH domain and N-terminal amphipathic helix, positioning the adaptor at
    clathrin-coated pits where it senses and drives curvature during coated-vesicle 
    maturation.
  directly_involved_in:
  - id: GO:0097753
    label: membrane bending
  - id: GO:0097494
    label: regulation of vesicle size
  - id: GO:0006900
    label: vesicle budding from membrane
  - id: GO:0072583
    label: clathrin-dependent endocytosis
  locations:
  - id: GO:0005905
    label: clathrin-coated pit
  - id: GO:0030136
    label: clathrin-coated vesicle
  - id: GO:0005886
    label: plasma membrane
  - id: GO:0005829
    label: cytosol
  supported_by:
  - reference_id: PMID:25898166
    supporting_text: CALM is thus a major factor in controlling CCV size and maturation
  - reference_id: PMID:25898166
    supporting_text: Here we show that CALM possesses an N-terminal amphipathic helix 
      that regulates CCP/CCV size and maturation and hence endocytic rate
- molecular_function:
    id: GO:0030276
    label: clathrin binding
  description: PICALM binds clathrin heavy chain and AP-2-associated endocytic machinery
    to promote clathrin recruitment, clathrin coat assembly, and receptor/cargo 
    internalization at plasma membrane coated pits and related Golgi/endosomal sites.
  directly_involved_in:
  - id: GO:0048268
    label: clathrin coat assembly
  - id: GO:0072583
    label: clathrin-dependent endocytosis
  - id: GO:0006898
    label: receptor-mediated endocytosis
  - id: GO:0031623
    label: receptor internalization
  locations:
  - id: GO:0005905
    label: clathrin-coated pit
  - id: GO:0030136
    label: clathrin-coated vesicle
  - id: GO:0005794
    label: Golgi apparatus
  supported_by:
  - reference_id: PMID:10436022
    supporting_text: the clathrin heavy chain is the major binding partner of CALM
  - reference_id: PMID:10436022
    supporting_text: Altogether, the data suggest that CALM is an important component of
      coated pit internalization machinery
  - reference_id: PMID:16262731
    supporting_text: critical role for CALM in the regulation and orderly progression of
      coated bud formation at the plasma membrane
- molecular_function:
    id: GO:0000149
    label: SNARE binding
  description: PICALM directly recognizes small R-SNARE cargoes, including VAMP2, VAMP3,
    and VAMP8, and sorts them into endocytic clathrin-coated vesicles for cycling 
    between the plasma membrane and endosomal/synaptic-vesicle compartments.
  directly_involved_in:
  - id: GO:0072583
    label: clathrin-dependent endocytosis
  - id: GO:0035459
    label: vesicle cargo loading
  - id: GO:0016188
    label: synaptic vesicle maturation
  - id: GO:0016197
    label: endosomal transport
  locations:
  - id: GO:0008021
    label: synaptic vesicle
  - id: GO:0042734
    label: presynaptic membrane
  - id: GO:0070381
    label: endosome to plasma membrane transport vesicle
  - id: GO:0005769
    label: early endosome
  - id: GO:0030136
    label: clathrin-coated vesicle
  supported_by:
  - reference_id: PMID:22118466
    supporting_text: prevents R-SNARE endocytosis in vivo
  - reference_id: PMID:22118466
    supporting_text: CALM:R-SNARE interactions ensure that R-SNAREs
proposed_new_terms: []
suggested_questions:
- question: Should amyloid-beta/LRP1 transcytosis annotations be represented as 
    cargo-specific receptor internalization/transcytosis rather than direct amyloid-beta
    binding by PICALM?
  experts:
  - Alzheimer BBB trafficking experts
  - GO endocytosis curators
- question: Which PICALM isoforms or tissue contexts should be distinguished for 
    neuronal SNARE sorting, endothelial amyloid-beta clearance, erythroid transferrin 
    receptor uptake, and nuclear/leukemia-associated localization?
  experts:
  - PICALM/CALM domain experts
  - GO isoform annotation curators
suggested_experiments:
- description: Rescue PICALM-null human neurons, endothelial cells, and erythroid 
    precursors with endogenous-level wild-type, PIP2-binding-defective, 
    clathrin-binding-defective, and SNARE-binding-defective PICALM variants, then 
    quantify clathrin-coated pit maturation, VAMP cargo sorting, LRP1/amyloid-beta 
    transcytosis, and transferrin receptor uptake.
  hypothesis: PIP2/membrane-curvature, clathrin, and SNARE-binding modules make 
    separable contributions to shared endocytic adaptor function and tissue-specific 
    cargo phenotypes.
  experiment_type: endogenous-rescue separation-of-function trafficking assay
- description: Test whether PICALM directly binds amyloid-beta or instead binds 
    LRP1/cargo complexes during endothelial transcytosis using purified components, 
    LRP1-tail mutants, and live-cell cargo uptake assays.
  hypothesis: PICALM promotes amyloid-beta clearance primarily by recognizing LRP1/cargo
    endocytic machinery rather than by direct amyloid-beta binding.
  experiment_type: cargo-binding and endothelial transcytosis mechanism assay