GPHN

Existing Annotations Review

GO Term	Evidence	Action	Reason
GO:0005737 cytoplasm	IBA GO_REF:0000033	KEEP AS NON CORE	Summary: Gephyrin is a cytoplasmic/cytosolic peripheral membrane protein; the phylogenetic inference is consistent with the experimental cytosol annotation. "cytoplasm" is a very general parent of the more specific cytosol location that is directly supported. Reason: Correct but non-informative parent location; the specific cytosol/postsynaptic-membrane localizations carry the core-relevant information.
GO:0005829 cytosol	IBA GO_REF:0000033	ACCEPT	Summary: Cytosolic localization is directly supported experimentally in non-neuronal cells, where the enzymatic MoCo function is exerted. Reason: Consistent with IDA evidence (PMID:22270318) and with the site of the MoCo-biosynthetic activity.
GO:0045211 postsynaptic membrane	IBA GO_REF:0000033	ACCEPT	Summary: Gephyrin acts at the cytoplasmic face of the inhibitory postsynaptic membrane where it clusters GlyR and GABAAR; phylogenetic inference agrees with the human IDA evidence. Reason: Core location for the synaptic scaffolding function; supported by IDA (PMID:25025157, PMID:26613940).
GO:0072579 glycine receptor clustering	IBA GO_REF:0000033	ACCEPT	Summary: Clustering of glycine receptors at glycinergic postsynapses is a classical, defining gephyrin function conserved across vertebrates. Reason: Core synaptic-scaffold process; strongly supported by orthologue data and the human literature (UniProt FUNCTION; PMID:26613940).
GO:0006777 Mo-molybdopterin cofactor biosynthetic process	IBA GO_REF:0000033	ACCEPT	Summary: Participation in Mo-molybdopterin cofactor biosynthesis is a core, deeply conserved function of gephyrin and its orthologues. Reason: Core enzymatic process; supported experimentally in human (IMP PMID:9990024, IDA PMID:26613940).
GO:0030425 dendrite	IBA GO_REF:0000033	KEEP AS NON CORE	Summary: Neuronal gephyrin localizes to dendrites where it forms inhibitory postsynaptic clusters. Reason: Correct cell-projection location supporting the synaptic role; more informative than the generic cytoplasm term but subordinate to postsynaptic membrane as the core site.
GO:0099572 postsynaptic specialization	IBA GO_REF:0000033	KEEP AS NON CORE	Summary: Gephyrin is a component of the inhibitory postsynaptic specialization/density where it scaffolds receptors. Reason: Consistent with the scaffold role and with ISS postsynaptic density annotations; a valid but less specific companion to postsynaptic membrane.
GO:0061599 molybdopterin molybdotransferase activity	IBA GO_REF:0000033	ACCEPT	Summary: The C-terminal E domain of gephyrin catalyses molybdenum insertion into adenylyl- molybdopterin (EC 2.10.1.1), the final step of MoCo synthesis; this is one of the two core catalytic activities. Reason: Core molecular function; supported by UniProt catalytic activity and experimental data (PMID:23163752, PMID:26613940).
GO:0007529 establishment of synaptic specificity at neuromuscular junction	IBA GO_REF:0000033	MARK AS OVER ANNOTATED	Summary: This term derives from invertebrate/lower-vertebrate orthologue phenotypes at the NMJ. Human gephyrin acts at central inhibitory synapses (glycinergic/GABAergic), not at the cholinergic NMJ, so this is an over-broad phylogenetic transfer for the human gene. Reason: No human evidence for an NMJ-synaptic-specificity role; likely over-propagated from orthologues in other lineages. Propagation Review Root cause: PROPAGATION BAD Failure modes: CONTEXT OR TISSUE MISMATCH
GO:0097112 gamma-aminobutyric acid receptor clustering	IBA GO_REF:0000033	ACCEPT	Summary: Gephyrin clusters major subsets of GABA type A receptors at inhibitory postsynapses; a core synaptic-scaffold process directly demonstrated in human/mammalian neurons. Reason: Core process; also supported by human IMP and IDA (PMID:25025157, PMID:26613940).
GO:0003824 catalytic activity	IEA GO_REF:0000117	MARK AS OVER ANNOTATED	Summary: Gephyrin is catalytic, but this root-level term conveys no specific information. The two specific catalytic activities (GO:0061598, GO:0061599) are separately annotated. Reason: Uninformative generic ARBA prediction superseded by the specific MoCo-biosynthesis MF terms.
GO:0005829 cytosol	IEA GO_REF:0000044	ACCEPT	Summary: Cytosolic localization; redundant with the experimental IDA cytosol annotation. Reason: Correct location, corroborated by IDA (PMID:22270318).
GO:0005856 cytoskeleton	IEA GO_REF:0000044	KEEP AS NON CORE	Summary: Gephyrin is a microtubule-associated protein that links receptors to the subsynaptic cytoskeleton, so cytoskeletal association is consistent with its scaffold role. Reason: Reasonable subcellular-location keyword mapping; supporting for the scaffold function but not itself a core term.
GO:0005886 plasma membrane	IEA GO_REF:0000120	KEEP AS NON CORE	Summary: As a peripheral, lipid-anchored membrane protein gephyrin associates with the cytoplasmic face of the (postsynaptic) plasma membrane; the specific postsynaptic-membrane term is the informative one. Reason: Correct but generic; subordinate to postsynaptic membrane.
GO:0006777 Mo-molybdopterin cofactor biosynthetic process	IEA GO_REF:0000120	ACCEPT	Summary: Duplicate of the experimentally supported MoCo biosynthetic process annotation. Reason: Core process, redundant with IMP/IDA/IBA evidence.
GO:0014069 postsynaptic density	IEA GO_REF:0000044	KEEP AS NON CORE	Summary: Gephyrin is part of the inhibitory postsynaptic density/specialization. Reason: Consistent with ISS postsynaptic density annotations; companion to postsynaptic membrane.
GO:0030425 dendrite	IEA GO_REF:0000044	KEEP AS NON CORE	Summary: Dendritic localization; redundant with the IDA dendrite annotation. Reason: Correct location supporting the synaptic role.
GO:0032324 molybdopterin cofactor biosynthetic process	IEA GO_REF:0000002	MODIFY	Summary: Sibling/related term to Mo-molybdopterin cofactor biosynthetic process (GO:0006777). The MoCo-specific term (GO:0006777) is the one directly supported by experiment. Reason: Generalize/normalize to the specifically supported GO:0006777 Mo-molybdopterin cofactor biosynthetic process already annotated with experimental evidence. Proposed replacements: Mo-molybdopterin cofactor biosynthetic process
GO:0045211 postsynaptic membrane	IEA GO_REF:0000044	ACCEPT	Summary: Postsynaptic membrane localization; redundant with the human IDA evidence. Reason: Core location for the scaffold function (IDA PMID:25025157, PMID:26613940).
GO:0050808 synapse organization	IEA GO_REF:0000117	MARK AS OVER ANNOTATED	Summary: Gephyrin does organize inhibitory synapses, but this is a broad parent of the specific receptor-clustering processes (GO:0072579, GO:0097112) that are experimentally annotated. Reason: Over-general ARBA term superseded by the specific glycine/GABAAR receptor-clustering annotations.
GO:0061598 molybdopterin adenylyltransferase activity	IEA GO_REF:0000120	ACCEPT	Summary: The G domain of gephyrin adenylylates molybdopterin (EC 2.7.7.75), the first of the two gephyrin-catalysed MoCo-biosynthesis steps; a core catalytic activity. Reason: Core molecular function; supported by UniProt catalytic activity and experimental data (PMID:23163752, PMID:26613940).
GO:0061599 molybdopterin molybdotransferase activity	IEA GO_REF:0000120	ACCEPT	Summary: Molybdenum-insertase activity of the E domain; duplicate of the IBA/ISS-supported core MF. Reason: Core molecular function, redundant with experimental/ISS evidence.
GO:0072657 protein localization to membrane	IEA GO_REF:0000117	MARK AS OVER ANNOTATED	Summary: Gephyrin localizes receptors to the postsynaptic membrane, but this generic ARBA term is a weak generalization of the specific receptor-clustering/adaptor functions. Reason: Over-general; the specific receptor-clustering and adaptor-activity annotations capture the biology more precisely.
GO:0005515 protein binding	IPI PMID:21094642 Structural models of DYNLL1 with interacting partners: Afric...	MARK AS OVER ANNOTATED	Summary: IPI interaction with DYNLL1 (dynein light chain LC8, P63167). Bare "protein binding" is uninformative about function; the specific interactions relevant to gephyrin's roles are captured in core functions and notes. Reason: Uninformative MF term (per curation guidelines); retained as evidence of the DYNLL1 interaction but not a core function.
GO:0005515 protein binding	IPI PMID:27173435 An organelle-specific protein landscape identifies novel dis...	MARK AS OVER ANNOTATED	Summary: IPI interaction (DYNLL1, P63167) from a large-scale organelle/interactome proteomics map. Bare "protein binding" is uninformative. Reason: Uninformative MF term; high-throughput interaction evidence only.
GO:0005515 protein binding	IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling...	MARK AS OVER ANNOTATED	Summary: IPI interaction (DYNLL1, P63167) from the BioPlex dual proteome-scale interactome. Bare "protein binding" is uninformative. Reason: Uninformative MF term; high-throughput interaction evidence only.
GO:0005515 protein binding	IPI PMID:35271311 OpenCell: Endogenous tagging for the cartography of human ce...	MARK AS OVER ANNOTATED	Summary: IPI interaction (DYNLL1, P63167) from the OpenCell endogenous-tagging interactome. Bare "protein binding" is uninformative. Reason: Uninformative MF term; high-throughput interaction evidence only.
GO:0005515 protein binding	IPI PMID:40205054 Multimodal cell maps as a foundation for structural and func...	MARK AS OVER ANNOTATED	Summary: IPI interaction (DYNLL1, P63167) from a multimodal cell-map interactome. Bare "protein binding" is uninformative. Reason: Uninformative MF term; high-throughput interaction evidence only.
GO:0005102 signaling receptor binding	IEA GO_REF:0000107	MARK AS OVER ANNOTATED	Summary: Gephyrin binds the intracellular loops of GlyR and GABAAR subunits; these are ligand-gated ion-channel receptors. "signaling receptor binding" is a plausible but non-specific Ensembl-projected term; the functionally meaningful annotations are the receptor-clustering processes and the adaptor activity. Reason: Non-specific binding term; the receptor-clustering BP terms better express the biology.
GO:0005737 cytoplasm	IEA GO_REF:0000120	KEEP AS NON CORE	Summary: Generic cytoplasm location; redundant with the cytosol annotations. Reason: Correct but non-informative parent location.
GO:0007416 synapse assembly	IEA GO_REF:0000107	MARK AS OVER ANNOTATED	Summary: Gephyrin contributes to inhibitory postsynapse assembly, but the specific receptor- clustering processes are the experimentally supported terms; this Ensembl-projected term is a broad generalization. Reason: Over-general; superseded by the specific receptor-clustering annotations.
GO:0009898 cytoplasmic side of plasma membrane	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Gephyrin is a lipid-anchored peripheral protein on the cytoplasmic face of the (postsynaptic) membrane, consistent with UniProt topology. Reason: Accurate topology detail supporting the postsynaptic-membrane localization.
GO:0042802 identical protein binding	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Gephyrin self-oligomerizes (homotrimer via G domain, homodimer via E domain, higher-order lattices), which underlies its scaffolding; self-association is experimentally documented. Reason: Correct self-interaction supported by IDA (PMID:25025157) and UniProt SUBUNIT; relevant to, but not itself, the core scaffold function.
GO:0045184 establishment of protein localization	IEA GO_REF:0000107	MARK AS OVER ANNOTATED	Summary: Very broad process term projected from orthologue; the specific receptor-clustering and adaptor annotations capture gephyrin's localization role. Reason: Over-general; superseded by specific receptor-clustering/adaptor annotations.
GO:0060077 inhibitory synapse	IEA GO_REF:0000107	ACCEPT	Summary: Gephyrin is the defining scaffold of inhibitory (glycinergic/GABAergic) synapses; this is an accurate location. Reason: Correct and informative synapse-type location for the core scaffold function.
GO:0060090 molecular adaptor activity	IEA GO_REF:0000107	MODIFY	Summary: Gephyrin acts as a molecular adaptor bridging inhibitory receptors to the cytoskeleton; this is directly supported by the IMP protein-macromolecule adaptor activity annotation (GO:0030674), a child of this term. Reason: Use the more specific, experimentally supported child term protein-macromolecule adaptor activity (GO:0030674). Proposed replacements: protein-macromolecule adaptor activity
GO:0098794 postsynapse	IEA GO_REF:0000120	KEEP AS NON CORE	Summary: Postsynaptic localization; broad parent of the specific postsynaptic-membrane term. Reason: Correct but generic; subordinate to postsynaptic membrane.
GO:0098982 GABA-ergic synapse	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Gephyrin scaffolds GABAAR at GABAergic synapses; an accurate synapse-type location. Reason: Correct location supporting the GABAAR-clustering role; companion to inhibitory synapse.
GO:0005829 cytosol	IDA GO_REF:0000052	ACCEPT	Summary: Immunofluorescence (HPA) cytosolic localization, consistent with the non-neuronal cytosolic pool where the MoCo enzymatic function operates. Reason: Experimentally supported cytosol location.
GO:0005886 plasma membrane	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: ISS from rat orthologue (Q03555); gephyrin is a peripheral membrane protein. The specific postsynaptic-membrane term is the informative one. Reason: Correct but generic membrane location.
GO:0014069 postsynaptic density	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: ISS postsynaptic density localization from mouse orthologue (Q8BUV3); consistent with gephyrin as an inhibitory postsynaptic-density scaffold. Reason: Supporting location for the scaffold role.
GO:0006777 Mo-molybdopterin cofactor biosynthetic process	IMP PMID:9990024 The neurotransmitter receptor-anchoring protein gephyrin rec...	ACCEPT	Summary: Foundational experimental evidence that gephyrin functions in MoCo biosynthesis: gephyrin reconstitutes MoCo synthesis in MoCo-deficient bacteria, a molybdenum-dependent mouse cell line and a MoCo-deficient plant, and antisense knockdown reduces cellular MoCo content. Reason: Core enzymatic process, directly supported. Supporting Evidence: PMID:9990024 gephyrin expression can reconstitute Moco
GO:0061598 molybdopterin adenylyltransferase activity	ISS GO_REF:0000024	ACCEPT	Summary: G-domain adenylyltransferase activity (first MoCo step), ISS from rat orthologue; a core catalytic function. Reason: Core molecular function.
GO:0061599 molybdopterin molybdotransferase activity	ISS GO_REF:0000024	ACCEPT	Summary: E-domain molybdotransferase (Mo-insertase) activity (final MoCo step), ISS from rat orthologue; a core catalytic function. Reason: Core molecular function.
GO:0061599 molybdopterin molybdotransferase activity	ISS PMID:23163752 Metal insertion into the molybdenum cofactor: product-substr...	ACCEPT	Summary: Belaidi & Schwarz reconstituted in-vitro MoCo synthesis and showed the E domain catalyses metal insertion in an ATP-dependent manner, with over 300-fold higher activity for the fused (full-length) protein via product-substrate channelling. Reason: Core molecular function; directly supported. Supporting Evidence: PMID:23163752 E domain, which catalyses the metal insertion
GO:0005829 cytosol	IDA PMID:22270318 Expression and subcellular distribution of gephyrin in non-n...	ACCEPT	Summary: Immunofluorescence and subcellular fractionation showed gephyrin localizes to the cytoplasm of hepatocytes and cultured non-neuronal cells, where its metabolic MoCo function is exerted. Reason: Experimentally supported cytosol location for the non-neuronal/metabolic pool. Supporting Evidence: PMID:22270318 gephyrin localizes to the cytoplasm of both tissue hepatocytes and cultured
GO:0006777 Mo-molybdopterin cofactor biosynthetic process	IDA PMID:26613940 Simultaneous impairment of neuronal and metabolic function o...	ACCEPT	Summary: Purified gephyrin synthesized MoCo in vitro, whereas the disease variant G375D was enzymatically inactive and unable to catalyze MoCo biosynthesis, directly demonstrating the MoCo-biosynthetic function of human gephyrin. Reason: Core enzymatic process, directly supported. Supporting Evidence: PMID:26613940 enzymatically inactive and unable to catalyze MoCo biosynthesis
GO:0030674 protein-macromolecule adaptor activity	IMP PMID:25025157 Palmitoylation of gephyrin controls receptor clustering and ...	ACCEPT	Summary: Gephyrin bridges inhibitory receptors to the postsynaptic membrane/cytoskeleton; mutation of palmitoylation sites Cys212/Cys284 impairs membrane association and receptor clustering, supporting its adaptor/scaffold activity. Reason: Core molecular function representing the synaptic-scaffold role; experimentally supported. Supporting Evidence: PMID:25025157 palmitoylation of gephyrin is essential for postsynaptic cluster formation in neurons
GO:0043197 dendritic spine	IDA PMID:25025157 Palmitoylation of gephyrin controls receptor clustering and ...	KEEP AS NON CORE	Summary: Gephyrin clusters were imaged along dendrites/dendritic segments in hippocampal neurons. Reason: Accurate neuronal cell-projection location supporting the scaffold role; subordinate to postsynaptic membrane.
GO:0045211 postsynaptic membrane	IDA PMID:25025157 Palmitoylation of gephyrin controls receptor clustering and ...	ACCEPT	Summary: Gephyrin is associated with, and clusters GABAARs at, the postsynaptic membrane; membrane association depends on palmitoylation at Cys212/Cys284. Reason: Core location for the scaffold function; directly supported. Supporting Evidence: PMID:25025157 Gephyrin anchors major subsets of GABAARs in the postsynaptic membrane
GO:0005829 cytosol	ISS GO_REF:0000024	ACCEPT	Summary: ISS cytosol from mouse orthologue (Q8BUV3); redundant with human IDA evidence. Reason: Correct location.
GO:0042802 identical protein binding	IDA PMID:25025157 Palmitoylation of gephyrin controls receptor clustering and ...	KEEP AS NON CORE	Summary: Gephyrin self-associates into hexamers/nonamers and higher-order clusters; oligomerization is documented in this study and is the structural basis of the postsynaptic lattice. Reason: Correct self-oligomerization; mechanistically relevant to the scaffold function but not a standalone core MF.
GO:0097060 synaptic membrane	IDA PMID:25025157 Palmitoylation of gephyrin controls receptor clustering and ...	KEEP AS NON CORE	Summary: Gephyrin was found mainly in the synaptosomal (membrane) fraction, localized at synaptic membranes. Reason: Correct location; parent of the more specific postsynaptic membrane term.
GO:0097112 gamma-aminobutyric acid receptor clustering	IMP PMID:25025157 Palmitoylation of gephyrin controls receptor clustering and ...	ACCEPT	Summary: Palmitoylation-deficient gephyrin (Cys212Ser/Cys284Ser) reduces gephyrin cluster size and surface GABAAR levels, showing gephyrin is required for GABAAR clustering. Reason: Core synaptic-scaffold process; directly supported. Supporting Evidence: PMID:25025157 palmitoylation of gephyrin is essential for postsynaptic cluster formation in neurons
GO:0097060 synaptic membrane	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: ISS synaptic membrane from mouse orthologue (Q8BUV3); redundant with human IDA. Reason: Correct location; parent of postsynaptic membrane.
GO:0008940 nitrate reductase activity	IMP PMID:9990024 The neurotransmitter receptor-anchoring protein gephyrin rec...	MARK AS OVER ANNOTATED	Summary: Nitrate reductase is a plant/fungal MoCo-dependent molybdoenzyme used as the readout in the Nia1 complementation assay; restoration of nitrate reductase activity reports that gephyrin reconstituted MoCo biosynthesis. Human gephyrin is not itself a nitrate reductase, so this is a mis-transfer of the assay readout to gephyrin's own molecular function. Reason: Experimental annotation retained per policy, but nitrate reductase activity is the reporter enzyme's function, not gephyrin's; gephyrin's true MF is MoCo biosynthesis (GO:0061598/ GO:0061599).
GO:0010038 response to metal ion	IMP PMID:9990024 The neurotransmitter receptor-anchoring protein gephyrin rec...	MARK AS OVER ANNOTATED	Summary: Gephyrin inserts molybdenum into molybdopterin and its activity is modulated by metals (inhibited by copper/tungsten), so a relationship to metal ions exists, but "response to metal ion" is a broad, indirect process term for what is fundamentally a MoCo-biosynthetic activity. Reason: Over-broad process; the molybdenum-insertion biology is captured by GO:0006777 and GO:0061599.
GO:0043546 molybdopterin cofactor binding	IDA PMID:9990024 The neurotransmitter receptor-anchoring protein gephyrin rec...	ACCEPT	Summary: Gephyrin binds molybdopterin (the metabolic precursor of MoCo) with high affinity, an activity central to its role as a MoCo-biosynthetic enzyme. Reason: Directly supported binding activity underpinning the enzymatic function. Supporting Evidence: PMID:9990024 gephyrin binds with high
GO:0030425 dendrite	IDA PMID:26613940 Simultaneous impairment of neuronal and metabolic function o...	KEEP AS NON CORE	Summary: WT gephyrin formed postsynaptic clusters along dendrites in hippocampal neurons (the G375D variant was instead diffusely distributed). Reason: Correct neuronal location; supporting for the scaffold role. Supporting Evidence: PMID:26613940 GFP‐G375D was diffusively distributed in neurons and filled all cellular compartments
GO:0097112 gamma-aminobutyric acid receptor clustering	IDA PMID:26613940 Simultaneous impairment of neuronal and metabolic function o...	ACCEPT	Summary: The G375D variant decreased cell-surface GABAAR clustering and mIPSC amplitude, whereas WT gephyrin supported GABAAR clustering, demonstrating gephyrin's role in GABAAR clustering. Reason: Core synaptic-scaffold process; directly supported. Supporting Evidence: PMID:26613940 Gephyrin is the major postsynaptic scaffolding protein at inhibitory synapses
GO:0005515 protein binding	IPI PMID:26613940 Simultaneous impairment of neuronal and metabolic function o...	MARK AS OVER ANNOTATED	Summary: IPI interactions with GABRA3 (P34903) and GLRB (P48167) underlying receptor clustering. Bare "protein binding" is uninformative; the specific interactions are captured in core functions and notes. Reason: Uninformative MF term per curation guidelines; the biologically meaningful GABRA3/GLRB binding informs the receptor-clustering core function.
GO:0045211 postsynaptic membrane	IDA PMID:26613940 Simultaneous impairment of neuronal and metabolic function o...	ACCEPT	Summary: WT gephyrin localizes to postsynaptic clusters at the membrane; the non-clustering G375D variant fails to do so. Reason: Core location for the scaffold function; directly supported. Supporting Evidence: PMID:26613940 Gephyrin forms multimeric complexes at postsynaptic membranes
GO:0005886 plasma membrane	TAS Reactome:R-HSA-947531	KEEP AS NON CORE	Summary: Reactome traceable-author-statement plasma-membrane localization; correct but generic relative to the specific postsynaptic-membrane term. Reason: Correct but generic membrane location.

Gene Description

Existing Annotations Review

Core Functions

Molybdopterin adenylyltransferase (G domain): adenylylates molybdopterin using ATP to form adenylyl-molybdopterin, the first of the two gephyrin-catalysed steps of molybdenum cofactor biosynthesis.

Molybdopterin molybdotransferase / molybdenum insertase (E domain): inserts molybdenum into adenylyl-molybdopterin to form the mature molybdenum cofactor with release of AMP, the final step of MoCo biosynthesis.

Inhibitory postsynaptic scaffold: acts as a protein-macromolecule adaptor that clusters glycine receptors and major subsets of GABA type A receptors at the postsynaptic membrane and anchors them to the cytoskeleton, organizing the inhibitory postsynapse.

Glycine receptor clustering at glycinergic postsynapses: the classical, deeply conserved scaffolding function by which gephyrin localizes and immobilizes glycine receptors at the inhibitory postsynaptic membrane.

References

📚 Additional Documentation

Notes

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