PRRT1

Existing Annotations Review

GO Term	Evidence	Action	Reason
GO:0030545 signaling receptor regulator activity	IBA GO_REF:0000033	ACCEPT	Summary: PRRT1/SynDIG4 directly modulates AMPA receptor (AMPAR) function as an auxiliary subunit. It binds to AMPAR complexes and regulates their gating properties, slowing deactivation and reducing desensitization. This constitutes regulation of a signaling receptor (AMPAR is an ionotropic glutamate receptor). The term is appropriate as PRRT1 modulates receptor activity rather than acting as the receptor itself (file:human/PRRT1/PRRT1-deep-research-falcon.md). Reason: SynDIG4 functions as an AMPAR auxiliary factor that co-purifies with native AMPAR complexes and modulates gating (file:human/PRRT1/PRRT1-deep-research-falcon.md). Evidence shows it slows deactivation of GluA1 homomers and GluA1/2 heteromers and reduces desensitization of GluA1. IBA annotations have undergone phylogenetic review and this function is well-supported by the conserved role across orthologs. Supporting Evidence: file:human/PRRT1/PRRT1-deep-research-falcon.md SynDIG4 co-purifies with native AMPAR complexes and modulates gating. Evidence indicates it slows deactivation of GluA1 homomers and GluA1/2 heteromers and reduces desensitization of GluA1
GO:0045211 postsynaptic membrane	IBA GO_REF:0000033	MODIFY	Summary: While PRRT1/SynDIG4 is present at synapses as part of AMPAR complexes, recent evidence indicates it is largely intracellular and enriched OUTSIDE the postsynaptic density (PSD). The protein localizes predominantly to endosomal compartments and extrasynaptic AMPAR pools rather than the postsynaptic membrane proper (file:human/PRRT1/PRRT1-deep-research-falcon.md). Reason: Literature shows SynDIG4 is "largely intracellular and enriched outside the postsynaptic density, with localization to endosomal compartments and extrasynaptic AMPAR pools" (file:human/PRRT1/PRRT1-deep-research-falcon.md). Quantitative colocalization data shows: vGLUT1 15.6%, GluA1 41.2%, transferrin receptor ~20%, EEA1 ~25%, Rab7 <10%, supporting enrichment in early/recycling pathways. Proposed replacements: recycling endosome early endosome Supporting Evidence: file:human/PRRT1/PRRT1-deep-research-falcon.md SynDIG4 is largely intracellular and enriched outside the postsynaptic density, with localization to endosomal compartments and extrasynaptic AMPAR pools. Quantitatively, reported colocalization values in neurons include vGLUT1 15.6%, GluA1 41.2%, transferrin receptor ~20%, EEA1 ~25%, and Rab7 <10%
GO:0050808 synapse organization	IBA GO_REF:0000033	ACCEPT	Summary: PRRT1/SynDIG4 plays a role in synapse organization through its regulation of AMPAR availability at synapses. The protein maintains extrasynaptic AMPAR pools which are necessary for synapse development and function. Knockout of SynDIG4 results in reduced synaptic surface GluA1 and impaired synaptic plasticity (file:human/PRRT1/PRRT1-deep-research-falcon.md). Reason: UniProt states PRRT1 is "Required to maintain a pool of extrasynaptic AMPA-regulated glutamate receptors which is necessary for synapse development and function" (UniProtKB:Q99946). SynDIG4 KO neurons show reduced synaptic surface GluA1 at baseline and impaired LTP/LTD, indicating a role in organizing functional synapses. Supporting Evidence: file:human/PRRT1/PRRT1-deep-research-falcon.md SynDIG4 KO neurons show reduced synaptic surface GluA1 at baseline
GO:0098978 glutamatergic synapse	IBA GO_REF:0000033	ACCEPT	Summary: PRRT1/SynDIG4 functions specifically at glutamatergic synapses as an auxiliary subunit of AMPA-type glutamate receptors. All functional studies demonstrate its role in regulating glutamatergic synaptic transmission (file:human/PRRT1/PRRT1-deep-research-falcon.md). Reason: SynDIG4/PRRT1 is exclusively associated with AMPAR complexes at excitatory glutamatergic synapses. The protein regulates AMPAR trafficking and gating, and SynDIG4 KO specifically affects glutamatergic transmission (LTP/LTD at hippocampal synapses). Supporting Evidence: file:human/PRRT1/PRRT1-deep-research-falcon.md SynDIG4 is an auxiliary protein which regulates trafficking, gating, and synaptic plasticity of AMPA-type receptors
GO:2000311 regulation of AMPA receptor activity	IBA GO_REF:0000033	ACCEPT	Summary: This is the core biological process annotation for PRRT1/SynDIG4. The protein directly regulates AMPAR activity through multiple mechanisms: modulating gating kinetics, controlling receptor trafficking and recycling, and maintaining surface AMPAR availability (file:human/PRRT1/PRRT1-deep-research-falcon.md). Reason: Extensive evidence supports SynDIG4 as a bona fide AMPAR auxiliary factor. It modulates AMPAR gating (slows deactivation, reduces desensitization), regulates AMPAR endocytic recycling via its YVPV motif, and maintains extrasynaptic/synaptic AMPAR pools through Rab4/Rab11 dynamics. This is the most precise annotation for the core function. Supporting Evidence: file:human/PRRT1/PRRT1-deep-research-falcon.md SynDIG4/PRRT1 functions as an AMPAR auxiliary factor that regulates receptor trafficking, surface/synaptic availability, and gating properties, thereby contributing to basal synaptic transmission and activity-dependent plasticity file:human/PRRT1/PRRT1-deep-research-falcon.md SynDIG4 contains a canonical tyrosine-based endocytic motif, 178-YVPV-181 (YxxPhi), which binds the AP-2 mu2 cargo-sorting subunit
GO:0005886 plasma membrane	IEA GO_REF:0000044	KEEP AS NON CORE	Summary: PRRT1/SynDIG4 is a transmembrane protein that does localize to the plasma membrane, but this annotation is overly broad. The protein cycles between plasma membrane and endosomal compartments, and is enriched in endosomes and extrasynaptic membrane pools rather than being a constitutive plasma membrane protein (file:human/PRRT1/PRRT1-deep-research-falcon.md). Reason: While PRRT1 does transit through the plasma membrane as a type II transmembrane protein, its primary functional localization is in endosomal compartments (early endosomes, recycling endosomes) where it regulates AMPAR recycling. The plasma membrane annotation is not wrong but does not capture the primary localization. Supporting Evidence: file:human/PRRT1/PRRT1-deep-research-falcon.md In hippocampal neurons, SynDIG4 localizes partially to early and recycling endosomes and regulates GluA1-containing AMPAR recycling under basal conditions
GO:0016020 membrane	IEA GO_REF:0000002	ACCEPT	Summary: This is a very broad cellular component annotation from InterPro domain mapping. PRRT1 is indeed a membrane protein with a transmembrane domain, so this is technically correct but uninformative. Reason: PRRT1 contains a transmembrane helix (residues 224-244 per UniProt FT annotation) and is classified as a single-pass type II membrane protein. The IEA annotation from InterPro is technically accurate, if broad. More specific annotations (recycling endosome, early endosome, glutamatergic synapse) provide better localization information.
GO:0045202 synapse	IEA GO_REF:0000044	KEEP AS NON CORE	Summary: PRRT1/SynDIG4 does localize to synapses as part of the AMPAR complex, but is more accurately described as being enriched at extrasynaptic sites and in endosomal compartments that support synaptic function (file:human/PRRT1/PRRT1-deep-research-falcon.md). Reason: UniProt subcellular location indicates "Synapse" but literature shows SynDIG4 is "enriched outside the postsynaptic density". While the protein affects synaptic function and synaptic AMPARs, its primary localization is extrasynaptic/endosomal. The broader "synapse" term is acceptable as a general descriptor but not a core localization. Supporting Evidence: file:human/PRRT1/PRRT1-deep-research-falcon.md SynDIG4 is largely intracellular and enriched outside the postsynaptic density, with localization to endosomal compartments and extrasynaptic AMPAR pools
GO:0030545 signaling receptor regulator activity	IEA GO_REF:0000107	ACCEPT	Summary: Duplicate of the IBA annotation (same GO term). This IEA annotation from Ensembl Compara transfer also supports the role of PRRT1 as an AMPAR regulator (file:human/PRRT1/PRRT1-deep-research-falcon.md). Reason: This annotation duplicates the IBA annotation for the same term. Both are valid and supported by the literature showing PRRT1 modulates AMPAR gating and activity. Duplicate annotations with different evidence codes are acceptable. Supporting Evidence: file:human/PRRT1/PRRT1-deep-research-falcon.md SynDIG4 co-purifies with native AMPAR complexes and modulates gating
GO:0030672 synaptic vesicle membrane	IEA GO_REF:0000107	REMOVE	Summary: This annotation appears to be incorrect. PRRT1/SynDIG4 is a postsynaptic protein associated with AMPAR complexes and postsynaptic endosomes. There is no evidence for localization to synaptic vesicle membrane, which is a presynaptic structure. Reason: All functional evidence for SynDIG4/PRRT1 places it at postsynaptic sites as an AMPAR auxiliary subunit. Synaptic vesicles are presynaptic organelles that release neurotransmitters. PRRT1 is not involved in neurotransmitter release or presynaptic function. This appears to be an erroneous orthology transfer - no primary literature supports synaptic vesicle localization.
GO:0034394 protein localization to cell surface	IEA GO_REF:0000107	ACCEPT	Summary: PRRT1/SynDIG4 promotes AMPAR surface expression. UniProt states it "promotes GRIA1 and GRIA2 cell surface expression." This annotation is appropriate as PRRT1 plays a role in localizing these receptor proteins to the cell surface (file:human/PRRT1/PRRT1-deep-research-falcon.md). Reason: UniProt annotation and literature support that PRRT1 promotes AMPAR surface expression. SynDIG4 regulates GluA1-containing AMPAR recycling which maintains surface receptor pools. KO neurons show "reduced synaptic surface GluA1 at baseline". The process annotation is appropriate. Supporting Evidence: file:human/PRRT1/PRRT1-deep-research-falcon.md SynDIG4 KO neurons show reduced synaptic surface GluA1 at baseline, consistent with a deficit in maintaining AMPARs at or near synapses via endosomal recycling
GO:0060292 long-term synaptic depression	IEA GO_REF:0000107	ACCEPT	Summary: PRRT1/SynDIG4 is required for NMDAR-dependent LTD. SynDIG4 KO mice show impaired LTD. This annotation is appropriate as the protein is involved in this form of synaptic plasticity (file:human/PRRT1/PRRT1-deep-research-falcon.md). Reason: Literature shows SynDIG4/PRRT1 is required for single-tetanus-induced LTP and is also implicated in NMDAR-dependent LTD; KO slices lose single-tetanus LTP and show impaired LTD. The involvement in LTD is mechanistically linked to regulation of AMPAR trafficking and recycling dynamics. Supporting Evidence: file:human/PRRT1/PRRT1-deep-research-falcon.md SynDIG4/PRRT1 is required for single-tetanus-induced LTP and is also implicated in NMDAR-dependent LTD; KO slices lose single-tetanus LTP and show impaired LTD
GO:0098839 postsynaptic density membrane	IEA GO_REF:0000107	MODIFY	Summary: This annotation conflicts with evidence that SynDIG4 is enriched OUTSIDE the postsynaptic density. While some protein may be present in the PSD as part of AMPAR complexes, the primary localization is extrasynaptic and endosomal (file:human/PRRT1/PRRT1-deep-research-falcon.md). Reason: Literature explicitly states SynDIG4 is "enriched outside the postsynaptic density, with localization to endosomal compartments and extrasynaptic AMPAR pools". Colocalization with vGLUT1 (a synaptic marker) is only 15.6%. The PSD membrane annotation overstates synaptic enrichment and should be replaced with more accurate endosomal localizations. Proposed replacements: recycling endosome early endosome postsynaptic recycling endosome Supporting Evidence: file:human/PRRT1/PRRT1-deep-research-falcon.md SynDIG4 is largely intracellular and enriched outside the postsynaptic density, with localization to endosomal compartments and extrasynaptic AMPAR pools. Quantitatively, reported colocalization values in neurons include vGLUT1 15.6%
GO:0098978 glutamatergic synapse	IEA GO_REF:0000107	ACCEPT	Summary: Duplicate of the IBA annotation. PRRT1/SynDIG4 functions at glutamatergic synapses as an AMPAR auxiliary subunit. This is well-supported (file:human/PRRT1/PRRT1-deep-research-falcon.md). Reason: This annotation duplicates the IBA annotation for glutamatergic synapse. Both are valid and supported by extensive literature showing SynDIG4 specifically regulates AMPAR function at excitatory glutamatergic synapses.
GO:0006468 protein phosphorylation	ISS GO_REF:0000024	REMOVE	Summary: PRRT1/SynDIG4 is NOT a kinase and does not directly catalyze protein phosphorylation. UniProt states it "Plays a role in regulating basal phosphorylation levels of glutamate receptor GRIA1" - this means it REGULATES phosphorylation indirectly (likely through AMPAR complex dynamics), not that it catalyzes the reaction. PRRT1 has no kinase domain. Reason: This is an over-annotation. The protein phosphorylation term (GO:0006468) implies direct involvement in the phosphorylation process. PRRT1 lacks any kinase domain and is a single-pass transmembrane protein that functions as an AMPAR auxiliary subunit. Its effect on GRIA1 phosphorylation levels is indirect, mediated through its effects on AMPAR trafficking and complex assembly. Annotation to "regulation of protein phosphorylation" would be more appropriate if needed, but even this may be too specific given the indirect mechanism.
GO:0034394 protein localization to cell surface	ISS GO_REF:0000024	ACCEPT	Summary: Duplicate of the IEA annotation (same GO term). PRRT1 promotes GRIA1/GRIA2 surface expression through its role in AMPAR recycling (file:human/PRRT1/PRRT1-deep-research-falcon.md). Reason: This ISS annotation duplicates the IEA annotation and is well-supported by UniProt function description ("promotes GRIA1 and GRIA2 cell surface expression") and literature showing SynDIG4 maintains surface AMPAR pools through endosomal recycling. Supporting Evidence: file:human/PRRT1/PRRT1-deep-research-falcon.md SynDIG4 KO neurons show reduced synaptic surface GluA1 at baseline, consistent with a deficit in maintaining AMPARs at or near synapses via endosomal recycling
GO:0060292 long-term synaptic depression	ISS GO_REF:0000024	ACCEPT	Summary: Duplicate of the IEA annotation. SynDIG4 KO impairs NMDAR-dependent LTD. This annotation is appropriate (file:human/PRRT1/PRRT1-deep-research-falcon.md). Reason: This ISS annotation duplicates the IEA annotation for LTD involvement. Literature supports that SynDIG4 is required for normal LTD. The mechanism involves regulation of AMPAR recycling dynamics that are required for LTD expression. Supporting Evidence: file:human/PRRT1/PRRT1-deep-research-falcon.md SynDIG4/PRRT1 is required for single-tetanus-induced LTP and is also implicated in NMDAR-dependent LTD; KO slices lose single-tetanus LTP and show impaired LTD
GO:2000311 regulation of AMPA receptor activity	ISS GO_REF:0000024	ACCEPT	Summary: Duplicate of the IBA annotation. This is the core function of PRRT1/SynDIG4 as an AMPAR auxiliary subunit (file:human/PRRT1/PRRT1-deep-research-falcon.md). Reason: This ISS annotation duplicates the IBA annotation for AMPAR regulation. This is the most accurate and specific annotation for PRRT1's core function as an AMPAR auxiliary subunit that modulates receptor gating and trafficking. Supporting Evidence: file:human/PRRT1/PRRT1-deep-research-falcon.md SynDIG4/PRRT1 functions as an AMPAR auxiliary factor that regulates receptor trafficking, surface/synaptic availability, and gating properties
GO:0060291 long-term synaptic potentiation	ISS GO_REF:0000024	NEW	Summary: SynDIG4/PRRT1 is required for single-tetanus-induced LTP. This is a key function that is well-documented but missing from the current annotation set (file:human/PRRT1/PRRT1-deep-research-falcon.md). Reason: Literature clearly shows SynDIG4/PRRT1 is required for single-tetanus-induced LTP and SD4-KO abolishes single-tetanus induced LTP. This is a core function of the protein that should be annotated. The mechanism involves regulation of calcium-permeable AMPAR recruitment and endosomal recycling dynamics. Supporting Evidence: file:human/PRRT1/PRRT1-deep-research-falcon.md SynDIG4/PRRT1 is required for single-tetanus-induced LTP and is also implicated in NMDAR-dependent LTD; KO slices lose single-tetanus LTP file:human/PRRT1/PRRT1-deep-research-falcon.md SD4-KO abolishes single-tetanus induced LTP and reduces extrasynaptic GluA1 pools
GO:0001881 receptor recycling	ISS GO_REF:0000024	NEW	Summary: A core function of SynDIG4/PRRT1 is regulating AMPAR recycling through endosomal compartments. This is a key function missing from current annotations (file:human/PRRT1/PRRT1-deep-research-falcon.md). Reason: Recent literature shows SynDIG4 contains a canonical YxxPhi endocytic motif (YVPV) that binds AP-2 and regulates AMPAR recycling. SynDIG4 KO does not alter baseline endocytosis but reduces recycling of GluA1-containing receptors. This receptor recycling function is central to the protein's role and should be annotated. Supporting Evidence: file:human/PRRT1/PRRT1-deep-research-falcon.md Knockout (KO) does not alter baseline endocytosis but reduces recycling of GluA1-containing receptors, leading to elevated intracellular GluA1/GluA2 file:human/PRRT1/PRRT1-deep-research-falcon.md SynDIG4 contains a canonical tyrosine-based endocytic motif, 178-YVPV-181 (YxxPhi), which binds the AP-2 mu2 cargo-sorting subunit
GO:0055037 recycling endosome	ISS GO_REF:0000024	NEW	Summary: SynDIG4/PRRT1 localizes to recycling endosomes where it regulates AMPAR recycling. This is a key localization missing from current annotations (file:human/PRRT1/PRRT1-deep-research-falcon.md). Reason: Literature shows in hippocampal neurons, SynDIG4 localizes partially to early and recycling endosomes. Colocalization data shows ~20% overlap with transferrin receptor and ~25% with EEA1. SynDIG4 regulates Rab4/Rab11 endosomal dynamics that maintain surface AMPARs. Supporting Evidence: file:human/PRRT1/PRRT1-deep-research-falcon.md In hippocampal neurons, SynDIG4 localizes partially to early and recycling endosomes and regulates GluA1-containing AMPAR recycling under basal conditions file:human/PRRT1/PRRT1-deep-research-falcon.md Reported colocalization values in neurons include transferrin receptor ~20%, EEA1 ~25%

Gene Description

Existing Annotations Review

Core Functions

References

Deep Research

Falcon

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