ERC1

Existing Annotations Review

GO Term	Evidence	Action	Reason
GO:0098831 presynaptic active zone cytoplasmic component	IBA GO_REF:0000033	ACCEPT	Summary: ERC1/ELKS is a well-established component of the presynaptic active zone cytomatrix. The brain-specific ERC1b isoform is an insoluble active zone component (PMID:12391317). ERC1 interacts with RIM, liprin-alpha, and other CAZ scaffolds (PMID:12923177). This IBA annotation is phylogenetically sound and supported by extensive literature. Reason: Presynaptic active zone localization is a core feature of ERC1 in neurons. IBA annotation is well-supported by direct experimental evidence from ortholog studies and phylogenetic analysis. Supporting Evidence: PMID:12391317 ERC1b is detectable only in brain, where it is both a cytosolic protein and an insoluble active zone component PMID:12923177 the interaction between ERC2 and liprin-alpha may be involved in the presynaptic localization of liprin-alpha and the molecular organization of presynaptic active zones
GO:0098882 structural constituent of presynaptic active zone	IBA GO_REF:0000033	ACCEPT	Summary: ERC1/ELKS functions as a structural scaffold at the presynaptic active zone, interacting with RIM, liprin-alpha, Bassoon/Piccolo, and other CAZ components to organize the release site architecture (PMID:12391317, PMID:12923177). The IBA annotation reflects the conserved structural scaffolding role across vertebrates. Reason: ERC1 is a scaffold protein whose primary molecular function at the active zone is structural organization of the release machinery. This is a core molecular function annotation. IBA is phylogenetically well-supported. Supporting Evidence: PMID:12391317 ERC1a and ERC1b/2 likely perform similar functions at distinct localizations, indicating unexpected connections between nonneuronal membrane traffic at the Golgi complex executed via Rab6 and neuronal membrane traffic at the active zone executed via RIMs
GO:0048790 maintenance of presynaptic active zone structure	IBA GO_REF:0000033	ACCEPT	Summary: ERC1/ELKS contributes to maintenance of presynaptic active zone structure through its scaffolding interactions with RIM, liprin-alpha, and other CAZ components (PMID:12391317, PMID:12923177). Recent work in human neurons shows that liprin-alpha recruits ELKS proteins to nascent synaptic contacts, and this is required for functional active zone assembly. Reason: Maintenance of presynaptic active zone structure is a core biological process for ERC1 in neurons. IBA annotation is phylogenetically sound and supported by the hierarchical assembly model where ELKS is recruited by liprin-alpha to build and maintain the active zone. Supporting Evidence: PMID:12391317 ERC1b is detectable only in brain, where it is both a cytosolic protein and an insoluble active zone component
GO:0000139 Golgi membrane	IEA GO_REF:0000044	ACCEPT	Summary: ERC1 is recruited to Golgi membranes by RAB6A in a GTP-dependent manner (UniProt, by similarity). This IEA annotation is based on UniProt subcellular location mapping and is consistent with ERC1's role as a Rab6 effector involved in Golgi-derived vesicle trafficking. Reason: Golgi membrane localization is consistent with ERC1's well-established role as a Rab6 effector that captures Rab6-positive Golgi-derived vesicles. The IEA mapping is appropriate.
GO:0002102 podosome	IEA GO_REF:0000044	KEEP AS NON CORE	Summary: ERC1 localizes to the cortex of myotube podosomes (UniProt, by similarity from mouse Q99MI1). This is an IEA annotation based on UniProt subcellular location vocabulary mapping. Reason: Podosome localization is supported by similarity data from mouse, but podosomes represent a specialized localization context rather than a core function of ERC1. The annotation is reasonable but non-core.
GO:0005737 cytoplasm	IEA GO_REF:0000044	ACCEPT	Summary: ERC1 is a cytoplasmic protein. Both the ubiquitous ERC1a isoform and the brain-specific ERC1b exist as cytosolic proteins (PMID:12391317). This IEA annotation is well-supported. Reason: Cytoplasmic localization is well-established for ERC1. The IEA mapping is appropriate and consistent with multiple experimental reports. Supporting Evidence: PMID:12391317 ERC1a is expressed ubiquitously as a cytosolic protein outside of brain; ERC1b is detectable only in brain, where it is both a cytosolic protein and an insoluble active zone component
GO:0005813 centrosome	IEA GO_REF:0000044	ACCEPT	Summary: ERC1 localizes to the centrosome, supported by immunofluorescence data showing 85% colocalization with gamma-tubulin in non-ciliated hTERT-RPE1 cells (PMID:27224062). This IEA annotation is consistent with the experimental IDA annotations from the same reference. Reason: Centrosome localization is experimentally validated. The IEA annotation is redundant with IDA evidence but acceptable.
GO:0015031 protein transport	IEA GO_REF:0000043	ACCEPT	Summary: ERC1 is involved in protein/vesicle transport as a Rab6 effector that captures Rab6-positive secretory vesicles at membrane-proximal platforms. The IEA annotation is based on UniProt keyword mapping. Reason: ERC1 has a well-established role in vesicular transport as a Rab6 effector and scaffold for secretion platforms. While the term is broad, it correctly captures a core aspect of ERC1 function.
GO:0016020 membrane	IEA GO_REF:0000044	ACCEPT	Summary: ERC1 is a peripheral membrane protein associated with Golgi membranes (via Rab6) and presynaptic membranes. This very broad IEA annotation captures the membrane association. Reason: ERC1 is indeed membrane-associated as a peripheral membrane protein at multiple compartments. The term is very broad but not incorrect.
GO:0042734 presynaptic membrane	IEA GO_REF:0000044	ACCEPT	Summary: ERC1 localizes to the presynaptic membrane region as part of the active zone scaffold. This IEA annotation is consistent with direct evidence from PMID:12391317. Reason: Presynaptic membrane localization is well-supported for brain-specific ERC1 isoforms. The IEA mapping is appropriate.
GO:0098793 presynapse	IEA GO_REF:0000117	ACCEPT	Summary: ERC1 localizes to the presynapse as part of the active zone cytomatrix. This IEA annotation from ARBA machine learning is consistent with extensive literature on ERC1/ELKS at presynaptic sites. Reason: Presynaptic localization is a well-established core feature of ERC1 in neurons. The IEA annotation is appropriate.
GO:0005515 protein binding	IPI PMID:15324660 Proteomic, functional, and domain-based analysis of in vivo ...	MARK AS OVER ANNOTATED	Summary: ERC1 was identified as a 14-3-3 binding protein in a large-scale proteomic study (PMID:15324660). This is a high-throughput protein binding annotation. Reason: Generic protein binding is uninformative for ERC1. The 14-3-3 interaction from a large-scale screen does not provide insight into ERC1's specific molecular function. A more specific MF term would be preferred. Supporting Evidence: PMID:15324660 Proteomic, functional, and domain-based analysis of in vivo 14-3-3 binding proteins involved in cytoskeletal regulation and cellular organization.
GO:0005515 protein binding	IPI PMID:17353931 Large-scale mapping of human protein-protein interactions by...	MARK AS OVER ANNOTATED	Summary: ERC1 was identified in a large-scale mapping of human protein-protein interactions by mass spectrometry (PMID:17353931). Generic protein binding from high-throughput data. Reason: Generic protein binding from high-throughput mass spectrometry. Not informative about specific molecular function. Supporting Evidence: PMID:17353931 Large-scale mapping of human protein-protein interactions by mass spectrometry.
GO:0005515 protein binding	IPI PMID:28514442 Architecture of the human interactome defines protein commun...	MARK AS OVER ANNOTATED	Summary: High-throughput interactome study identifying ERC1 protein interactions. Reason: Generic protein binding from high-throughput interactome mapping. Not informative about specific molecular function. Supporting Evidence: PMID:28514442 Architecture of the human interactome defines protein communities and disease networks.
GO:0005515 protein binding	IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling...	MARK AS OVER ANNOTATED	Summary: High-throughput dual proteome-scale network study. Reason: Generic protein binding from high-throughput study. Not informative about specific molecular function of ERC1. Supporting Evidence: PMID:33961781 2021 May 6. Dual proteome-scale networks reveal cell-specific remodeling of the human interactome.
GO:0005515 protein binding	IPI PMID:35271311 OpenCell: Endogenous tagging for the cartography of human ce...	MARK AS OVER ANNOTATED	Summary: OpenCell endogenous tagging study mapping cellular organization. Reason: Generic protein binding from high-throughput endogenous tagging study. Not informative about specific molecular function. Supporting Evidence: PMID:35271311 2022 Mar 11. OpenCell: Endogenous tagging for the cartography of human cellular organization.
GO:0005515 protein binding	IPI PMID:36931259 A central chaperone-like role for 14-3-3 proteins in human c...	MARK AS OVER ANNOTATED	Summary: ERC1 identified as a 14-3-3 binding protein in a study on 14-3-3 chaperone-like roles (PMID:36931259). Reason: Generic protein binding annotation. While 14-3-3 binding may be biologically relevant, the generic term does not capture specific function. Supporting Evidence: PMID:36931259 A central chaperone-like role for 14-3-3 proteins in human cells.
GO:0005515 protein binding	IPI PMID:27224062 SDCCAG8 Interacts with RAB Effector Proteins RABEP2 and ERC1...	MARK AS OVER ANNOTATED	Summary: ERC1 interacts with SDCCAG8 at the centrosome, demonstrated by co-immunoprecipitation and SILAC assay (PMID:27224062). This is a focused study identifying ERC1 as a specific SDCCAG8 interactor. Reason: While the SDCCAG8 interaction is well-supported by focused experimental data, the generic protein binding term is uninformative. The centrosome and ciliary basal body localization annotations from this study are more informative. Supporting Evidence: PMID:27224062 SDCCAG8 interacts with proteins of the centriolar satellites (OFD1, AZI1), of the endosomal sorting complex (RABEP2, ERC1), and with non-muscle myosin motor proteins (MYH9, MYH10, MYH14) at the centrosome
GO:0005515 protein binding	IPI PMID:12391317 A family of RIM-binding proteins regulated by alternative sp...	MARK AS OVER ANNOTATED	Summary: ERC1 binds to RIM proteins via its C-terminal PDZ-binding motif (PMID:12391317). The ERC1b isoform binds RIM while ERC1a does not. Both isoforms bind Rab6. Reason: The RIM and Rab6 binding interactions demonstrated in this paper are highly specific and important, but the generic protein binding term is uninformative. The PDZ domain binding and small GTPase binding annotations (ISS) better capture these specific interactions. Supporting Evidence: PMID:12391317 two related genes that encode proteins with identical C-terminal sequences that bind to the conserved PDZ domain of RIMs via an unusual PDZ-binding motif
GO:0005515 protein binding	IPI PMID:12923177 Interaction of the ERC family of RIM-binding proteins with t...	MARK AS OVER ANNOTATED	Summary: ERC1 directly interacts with liprin-alpha family proteins (PMID:12923177). Liprin-alpha1 associates with both ERC2 and ERC1b. Reason: The liprin-alpha interaction is important and specific, but generic protein binding is uninformative. The structural constituent and scaffolding annotations better capture ERC1's function. Supporting Evidence: PMID:12923177 liprin-alpha directly interacts with the ERC (ELKS-Rab6-interacting protein-CAST) family of proteins
GO:0043123 positive regulation of canonical NF-kappaB signal transduction	IDA PMID:15218148 Activation of transcription factor NF-kappaB requires ELKS, ...	KEEP AS NON CORE	Summary: Ducut Sigala et al. (2004) identified ELKS/ERC1 as an essential regulatory subunit of the IKK complex. Silencing ELKS by RNAi blocked induced expression of NF-kappaB target genes including IkappaBalpha, COX-2, and IL-8 (PMID:15218148). ELKS recruits IkappaBalpha to the IKK complex. Reason: The NF-kappaB regulatory role is experimentally validated by a high-quality study in Science. However, this function appears to be secondary to ERC1's primary role as a vesicular trafficking scaffold and active zone organizer. The deep research review notes that the NF-kappaB role is "suggestive but not definitive for functional annotation of ERC1's primary role." The annotation is retained as non-core. Supporting Evidence: PMID:15218148 We identified ELKS, an essential regulatory subunit of the IKK complex. Silencing ELKS expression by RNA interference blocked induced expression of NF-kappaB target genes
GO:0008385 IkappaB kinase complex	IDA PMID:15218148 Activation of transcription factor NF-kappaB requires ELKS, ...	KEEP AS NON CORE	Summary: ERC1/ELKS was shown to be part of the IKK complex, interacting with CHUK (IKKalpha), IKBKB (IKKbeta), and IKBKG (NEMO) (PMID:15218148). The interaction with IKBKG is independent of CHUK and IKBKB. Reason: IKK complex membership is experimentally demonstrated. However, this represents a secondary function of ERC1 rather than its primary scaffolding role at secretion/release sites. Retained as non-core. Supporting Evidence: PMID:15218148 ELKS, an essential regulatory subunit of the IKK complex
GO:0006355 regulation of DNA-templated transcription	IDA PMID:15218148 Activation of transcription factor NF-kappaB requires ELKS, ...	MARK AS OVER ANNOTATED	Summary: ERC1/ELKS regulates NF-kappaB-mediated transcription by functioning as a regulatory subunit of the IKK complex (PMID:15218148). Silencing ELKS blocked expression of NF-kappaB target genes. Reason: While ERC1 affects transcription through the NF-kappaB/IKK pathway, this annotation is overly broad. ERC1 is not a transcription factor or direct transcriptional regulator; it acts upstream through the IKK complex. The GO:0043123 (positive regulation of canonical NF-kappaB signal transduction) annotation already captures this more precisely. Supporting Evidence: PMID:15218148 Silencing ELKS expression by RNA interference blocked induced expression of NF-kappaB target genes
GO:0005813 centrosome	IDA GO_REF:0000052	ACCEPT	Summary: ERC1 centrosomal localization based on immunofluorescence data curation (GO_REF:0000052). Consistent with the experimental evidence from PMID:27224062 showing ERC1 colocalizes with gamma-tubulin at centrosomes. Reason: Centrosome localization is experimentally validated by immunofluorescence in hTERT-RPE1 cells (PMID:27224062). The annotation from immunofluorescence curation is well-supported.
GO:0005737 cytoplasm	IDA PMID:15218148 Activation of transcription factor NF-kappaB requires ELKS, ...	ACCEPT	Summary: ERC1/ELKS was shown to be a cytoplasmic protein in the Ducut Sigala et al. (2004) study characterizing its role in NF-kappaB signaling. Reason: Cytoplasmic localization is well-established for ERC1 across multiple studies.
GO:0005515 protein binding	IPI PMID:27224062 SDCCAG8 Interacts with RAB Effector Proteins RABEP2 and ERC1...	MARK AS OVER ANNOTATED	Summary: ERC1 interacts with SDCCAG8 at the centrosome, demonstrated by SILAC and co-immunoprecipitation (PMID:27224062). Reason: Duplicate of the protein binding annotation for PMID:27224062 reviewed above. Generic protein binding is uninformative. Supporting Evidence: PMID:27224062 SDCCAG8 interacts with proteins of the centriolar satellites (OFD1, AZI1), of the endosomal sorting complex (RABEP2, ERC1)
GO:0005813 centrosome	IDA PMID:27224062 SDCCAG8 Interacts with RAB Effector Proteins RABEP2 and ERC1...	ACCEPT	Summary: ERC1 localizes to centrosomes in hTERT-RPE1 cells, with 85% colocalization with gamma-tubulin in non-ciliated cells and 92% colocalization with polyglutamylated tubulin in ciliated cells (PMID:27224062). Reason: Centrosome localization is directly demonstrated by quantitative immunofluorescence analysis in a focused study. This is the first report of centriolar localization for ERC1. Supporting Evidence: PMID:27224062 RABEP2 and ERC1 localize to the centrioles of non-ciliated cells
GO:0036064 ciliary basal body	IDA PMID:27224062 SDCCAG8 Interacts with RAB Effector Proteins RABEP2 and ERC1...	KEEP AS NON CORE	Summary: ERC1 localizes to the ciliary basal body in ciliated hTERT-RPE1 cells, with 92% colocalization with polyglutamylated tubulin (PMID:27224062). This was the first report demonstrating centriolar/basal body localization for ERC1. Reason: Ciliary basal body localization is experimentally validated but represents a secondary localization context rather than a core function of ERC1. The primary roles of ERC1 are at active zones and plasma membrane-associated platforms. Supporting Evidence: PMID:27224062 ERC1 expression was retained at the basal body of ciliated cells
GO:0045296 cadherin binding	HDA PMID:25468996 E-cadherin interactome complexity and robustness resolved by...	UNDECIDED	Summary: ERC1 was identified as part of the E-cadherin interactome by quantitative proteomics (PMID:25468996). This is a high-throughput annotation. Reason: Cadherin binding from a high-throughput proteomic study. While ERC1's role at cortical platforms (PMAPs) could plausibly involve cadherin-associated complexes, direct cadherin binding has not been validated by focused studies. Unable to access the full text of PMID:25468996 to evaluate the strength of evidence. Supporting Evidence: PMID:25468996 E-cadherin interactome complexity and robustness resolved by quantitative proteomics.
GO:0002102 podosome	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: ERC1 localizes to the cortex of myotube podosomes, based on sequence similarity transfer from mouse ERC1 (Q99MI1). UniProt notes this localization by similarity. Reason: Podosome localization is supported by similarity from mouse data. However, podosomes are a specialized context and not a core localization for ERC1.
GO:0005737 cytoplasm	ISS GO_REF:0000024	ACCEPT	Summary: Cytoplasmic localization transferred by sequence similarity. Redundant with IDA evidence from PMID:15218148 and IEA annotation. Reason: Cytoplasmic localization is well-established for ERC1 from multiple sources. This ISS annotation is consistent with direct evidence.
GO:0030165 PDZ domain binding	ISS GO_REF:0000024	ACCEPT	Summary: ERC1 binds to the PDZ domain of RIM1/2 via its C-terminal IWA motif (isoform-dependent). The ERC1b isoform (brain-specific) has the RIM-binding C-terminus, while ERC1a does not (PMID:12391317). Reason: PDZ domain binding is a well-characterized molecular function of ERC1 (brain-specific isoforms) through its interaction with the RIM PDZ domain. This is more informative than generic protein binding and represents a core molecular function. Supporting Evidence: PMID:12391317 two related genes that encode proteins with identical C-terminal sequences that bind to the conserved PDZ domain of RIMs via an unusual PDZ-binding motif
GO:0031267 small GTPase binding	ISS GO_REF:0000024	ACCEPT	Summary: ERC1 binds active (GTP-bound) Rab6B via its C-terminal Rab6-binding domain (RBD, residues 849-922). The binding affinity is ~8 uM by ITC. Both ubiquitous and brain-specific ERC1 isoforms bind Rab6 (PMID:12391317). A 2.04 A crystal structure of the ELKS1 RBD/Rab6B complex has been solved. Reason: Small GTPase (Rab6) binding is a core molecular function of ERC1. The structural basis has been determined at atomic resolution, and the interaction is functionally important for vesicle capture at secretion platforms. ISS annotation is strongly supported by direct evidence from orthologs and recent structural studies. Supporting Evidence: PMID:12391317 both ubiquitous and brain-specific ERCs bind to Rab6, a GTP-binding protein involved in membrane traffic at the Golgi complex
GO:0042147 retrograde transport, endosome to Golgi	ISS GO_REF:0000024	MARK AS OVER ANNOTATED	Summary: ERC1 may be involved in Rab6-regulated endosome to Golgi transport, as suggested by its interaction with Rab6 (UniProt). However, the primary evidence supports ERC1's role in anterograde (Golgi-to-plasma membrane) vesicle transport rather than retrograde transport. Reason: The evidence primarily supports ERC1's role in anterograde secretory vesicle transport (capturing Rab6-positive Golgi-derived vesicles at plasma membrane platforms) rather than retrograde endosome-to-Golgi transport. While ERC1 interacts with Rab6 which is involved in retrograde transport, the functional evidence for ERC1 specifically in retrograde transport is weak. The annotation may be an over-interpretation of the Rab6 interaction. Supporting Evidence: PMID:12391317 both ubiquitous and brain-specific ERCs bind to Rab6, a GTP-binding protein involved in membrane traffic at the Golgi complex
GO:0045202 synapse	ISS GO_REF:0000024	ACCEPT	Summary: ERC1 localizes to synapses, specifically to the presynaptic active zone. Brain-specific isoforms (ERC1b) are active zone components (PMID:12391317). Reason: Synaptic localization is well-established for ERC1. This broader term is consistent with the more specific presynaptic active zone annotations.
GO:0042734 presynaptic membrane	TAS PMID:12391317 A family of RIM-binding proteins regulated by alternative sp...	ACCEPT	Summary: ERC1b localizes to the presynaptic membrane/active zone as established by Wang et al. (2002) (PMID:12391317). Reason: Presynaptic membrane localization for brain-specific ERC1 isoforms is directly supported by the cited reference. This is a core localization for neuronal ERC1 function. Supporting Evidence: PMID:12391317 ERC1b is detectable only in brain, where it is both a cytosolic protein and an insoluble active zone component
GO:0007252 I-kappaB phosphorylation	IDA PMID:15218148 Activation of transcription factor NF-kappaB requires ELKS, ...	NEW	Summary: ERC1/ELKS is required for IkappaB phosphorylation as a regulatory subunit of the IKK complex (PMID:15218148). This annotation appears in the UniProt GO cross-references but was not in the GOA export. Including for completeness. Reason: IkappaB phosphorylation is part of the NF-kappaB pathway function, which is a secondary function of ERC1. This annotation appears in UniProt GO cross-references but is not in the GOA export. Proposed as new annotation. Supporting Evidence: PMID:15218148 ELKS likely functions by recruiting IkappaBalpha to the IKK complex and thus serves a regulatory function for IKK activation

Gene Description

Existing Annotations Review

Core Functions

Structural scaffold at the presynaptic active zone, organizing the cytomatrix of the active zone (CAZ) by interacting with RIM, liprin-alpha, Bassoon, and Piccolo. Brain-specific ERC1b isoform binds RIM via C-terminal PDZ-binding motif and is an insoluble active zone component.

Regulatory subunit of the IKK complex facilitating NF-kappaB activation. ERC1/ELKS recruits IkappaBalpha to the IKK complex (CHUK, IKBKB, IKBKG), enabling IkappaBalpha phosphorylation and NF-kappaB-mediated transcription of inflammatory target genes. This is a secondary function of ERC1.

References

Deep Research

Falcon

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