id: Q8IUD2
gene_symbol: ERC1
product_type: PROTEIN
status: COMPLETE
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: >-
  ERC1 (also known as ELKS, RAB6IP2, CAST2) is a large coiled-coil scaffold/adaptor
  protein that organizes membrane-proximal secretion and synaptic release sites. It
  forms higher-order assemblies (plasma membrane-associated platforms, PMAPs) that
  capture Rab6-positive secretory carriers and recruit active-zone/cortical factors
  specifying vesicle docking and fusion locations. In neurons, ERC1 is a component of
  the cytomatrix at the active zone (CAZ), where it interacts with RIM, liprin-alpha,
  Bassoon, and Piccolo to scaffold neurotransmitter release machinery. In non-neuronal
  cells, ERC1 colocalizes with LL5-beta and CLASPs at cortical patches serving as
  preferential fusion sites for Rab6-positive vesicles. ERC1 binds active (GTP-bound)
  Rab6B via its C-terminal Rab6-binding domain (RBD, residues 849-922) and RIM via a
  C-terminal IWA/PDZ-binding motif (isoform-dependent). ERC1 also functions as a
  regulatory subunit of the IKK complex, recruiting IkappaBalpha to facilitate
  NF-kappaB activation. ERC1 localizes to centrosomes and ciliary basal bodies and
  interacts with SDCCAG8. Multiple isoforms exist; brain-specific isoforms (ERC1b)
  bind RIM and localize to active zones, while the ubiquitous isoform (ERC1a) does
  not bind RIM. ERC1 genomic rearrangements can create kinase fusion oncogenes
  (ERC1-RET, FGFR2-ERC1) in thyroid and lung carcinomas.
existing_annotations:
  # ===== IBA ANNOTATIONS =====
  - term:
      id: GO:0098831
      label: presynaptic active zone cytoplasmic component
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      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.
      action: ACCEPT
      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.
      supported_by:
        - reference_id: PMID:12391317
          supporting_text: "ERC1b is detectable only in brain, where it is both a cytosolic protein and an insoluble active zone component"
        - reference_id: PMID:12923177
          supporting_text: "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"

  - term:
      id: GO:0098882
      label: structural constituent of presynaptic active zone
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      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.
      action: ACCEPT
      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.
      supported_by:
        - reference_id: PMID:12391317
          supporting_text: "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"

  - term:
      id: GO:0048790
      label: maintenance of presynaptic active zone structure
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      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.
      action: ACCEPT
      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.
      supported_by:
        - reference_id: PMID:12391317
          supporting_text: "ERC1b is detectable only in brain, where it is both a cytosolic protein and an insoluble active zone component"

  # ===== IEA ANNOTATIONS =====
  - term:
      id: GO:0000139
      label: Golgi membrane
    evidence_type: IEA
    original_reference_id: GO_REF:0000044
    review:
      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.
      action: ACCEPT
      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.

  - term:
      id: GO:0002102
      label: podosome
    evidence_type: IEA
    original_reference_id: GO_REF:0000044
    review:
      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.
      action: KEEP_AS_NON_CORE
      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.

  - term:
      id: GO:0005737
      label: cytoplasm
    evidence_type: IEA
    original_reference_id: GO_REF:0000044
    review:
      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.
      action: ACCEPT
      reason: >-
        Cytoplasmic localization is well-established for ERC1. The IEA mapping is
        appropriate and consistent with multiple experimental reports.
      supported_by:
        - reference_id: PMID:12391317
          supporting_text: "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"

  - term:
      id: GO:0005813
      label: centrosome
    evidence_type: IEA
    original_reference_id: GO_REF:0000044
    review:
      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.
      action: ACCEPT
      reason: >-
        Centrosome localization is experimentally validated. The IEA annotation
        is redundant with IDA evidence but acceptable.

  - term:
      id: GO:0015031
      label: protein transport
    evidence_type: IEA
    original_reference_id: GO_REF:0000043
    review:
      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.
      action: ACCEPT
      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.

  - term:
      id: GO:0016020
      label: membrane
    evidence_type: IEA
    original_reference_id: GO_REF:0000044
    review:
      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.
      action: ACCEPT
      reason: >-
        ERC1 is indeed membrane-associated as a peripheral membrane protein at
        multiple compartments. The term is very broad but not incorrect.

  - term:
      id: GO:0042734
      label: presynaptic membrane
    evidence_type: IEA
    original_reference_id: GO_REF:0000044
    review:
      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.
      action: ACCEPT
      reason: >-
        Presynaptic membrane localization is well-supported for brain-specific
        ERC1 isoforms. The IEA mapping is appropriate.

  - term:
      id: GO:0098793
      label: presynapse
    evidence_type: IEA
    original_reference_id: GO_REF:0000117
    review:
      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.
      action: ACCEPT
      reason: >-
        Presynaptic localization is a well-established core feature of ERC1
        in neurons. The IEA annotation is appropriate.

  # ===== PROTEIN BINDING (IPI) ANNOTATIONS =====
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:15324660
    review:
      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.
      action: MARK_AS_OVER_ANNOTATED
      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.
      supported_by:
        - reference_id: PMID:15324660
          supporting_text: Proteomic, functional, and domain-based analysis of
            in vivo 14-3-3 binding proteins involved in cytoskeletal regulation
            and cellular organization.

  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:17353931
    review:
      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.
      action: MARK_AS_OVER_ANNOTATED
      reason: >-
        Generic protein binding from high-throughput mass spectrometry. Not
        informative about specific molecular function.
      supported_by:
        - reference_id: PMID:17353931
          supporting_text: Large-scale mapping of human protein-protein
            interactions by mass spectrometry.

  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:28514442
    review:
      summary: >-
        High-throughput interactome study identifying ERC1 protein interactions.
      action: MARK_AS_OVER_ANNOTATED
      reason: >-
        Generic protein binding from high-throughput interactome mapping. Not
        informative about specific molecular function.
      supported_by:
        - reference_id: PMID:28514442
          supporting_text: Architecture of the human interactome defines protein
            communities and disease networks.

  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:33961781
    review:
      summary: >-
        High-throughput dual proteome-scale network study.
      action: MARK_AS_OVER_ANNOTATED
      reason: >-
        Generic protein binding from high-throughput study. Not informative
        about specific molecular function of ERC1.
      supported_by:
        - reference_id: PMID:33961781
          supporting_text: 2021 May 6. Dual proteome-scale networks reveal
            cell-specific remodeling of the human interactome.

  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:35271311
    review:
      summary: >-
        OpenCell endogenous tagging study mapping cellular organization.
      action: MARK_AS_OVER_ANNOTATED
      reason: >-
        Generic protein binding from high-throughput endogenous tagging study.
        Not informative about specific molecular function.
      supported_by:
        - reference_id: PMID:35271311
          supporting_text: '2022 Mar 11. OpenCell: Endogenous tagging for the cartography
            of human cellular organization.'

  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:36931259
    review:
      summary: >-
        ERC1 identified as a 14-3-3 binding protein in a study on 14-3-3 chaperone-like
        roles (PMID:36931259).
      action: MARK_AS_OVER_ANNOTATED
      reason: >-
        Generic protein binding annotation. While 14-3-3 binding may be biologically
        relevant, the generic term does not capture specific function.
      supported_by:
        - reference_id: PMID:36931259
          supporting_text: A central chaperone-like role for 14-3-3 proteins in
            human cells.

  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:27224062
    review:
      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.
      action: MARK_AS_OVER_ANNOTATED
      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.
      supported_by:
        - reference_id: PMID:27224062
          supporting_text: "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"

  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:12391317
    review:
      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.
      action: MARK_AS_OVER_ANNOTATED
      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.
      supported_by:
        - reference_id: PMID:12391317
          supporting_text: "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"

  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:12923177
    review:
      summary: >-
        ERC1 directly interacts with liprin-alpha family proteins
        (PMID:12923177). Liprin-alpha1 associates with both ERC2 and ERC1b.
      action: MARK_AS_OVER_ANNOTATED
      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.
      supported_by:
        - reference_id: PMID:12923177
          supporting_text: "liprin-alpha directly interacts with the ERC (ELKS-Rab6-interacting protein-CAST) family of proteins"

  # ===== NF-kB PATHWAY ANNOTATIONS =====
  - term:
      id: GO:0043123
      label: positive regulation of canonical NF-kappaB signal transduction
    evidence_type: IDA
    original_reference_id: PMID:15218148
    review:
      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.
      action: KEEP_AS_NON_CORE
      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.
      supported_by:
        - reference_id: PMID:15218148
          supporting_text: "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"

  - term:
      id: GO:0008385
      label: IkappaB kinase complex
    evidence_type: IDA
    original_reference_id: PMID:15218148
    review:
      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.
      action: KEEP_AS_NON_CORE
      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.
      supported_by:
        - reference_id: PMID:15218148
          supporting_text: "ELKS, an essential regulatory subunit of the IKK complex"

  - term:
      id: GO:0006355
      label: regulation of DNA-templated transcription
    evidence_type: IDA
    original_reference_id: PMID:15218148
    review:
      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.
      action: MARK_AS_OVER_ANNOTATED
      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.
      supported_by:
        - reference_id: PMID:15218148
          supporting_text: "Silencing ELKS expression by RNA interference blocked induced expression of NF-kappaB target genes"

  # ===== IDA LOCALIZATION ANNOTATIONS =====
  - term:
      id: GO:0005813
      label: centrosome
    evidence_type: IDA
    original_reference_id: GO_REF:0000052
    review:
      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.
      action: ACCEPT
      reason: >-
        Centrosome localization is experimentally validated by immunofluorescence
        in hTERT-RPE1 cells (PMID:27224062). The annotation from immunofluorescence
        curation is well-supported.

  - term:
      id: GO:0005737
      label: cytoplasm
    evidence_type: IDA
    original_reference_id: PMID:15218148
    review:
      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.
      action: ACCEPT
      reason: >-
        Cytoplasmic localization is well-established for ERC1 across multiple studies.

  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:27224062
    review:
      summary: >-
        ERC1 interacts with SDCCAG8 at the centrosome, demonstrated by SILAC
        and co-immunoprecipitation (PMID:27224062).
      action: MARK_AS_OVER_ANNOTATED
      reason: >-
        Duplicate of the protein binding annotation for PMID:27224062 reviewed
        above. Generic protein binding is uninformative.
      supported_by:
        - reference_id: PMID:27224062
          supporting_text: "SDCCAG8 interacts with proteins of the centriolar satellites (OFD1, AZI1), of the endosomal sorting complex (RABEP2, ERC1)"

  - term:
      id: GO:0005813
      label: centrosome
    evidence_type: IDA
    original_reference_id: PMID:27224062
    review:
      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).
      action: ACCEPT
      reason: >-
        Centrosome localization is directly demonstrated by quantitative
        immunofluorescence analysis in a focused study. This is the first
        report of centriolar localization for ERC1.
      supported_by:
        - reference_id: PMID:27224062
          supporting_text: "RABEP2 and ERC1 localize to the centrioles of non-ciliated cells"

  - term:
      id: GO:0036064
      label: ciliary basal body
    evidence_type: IDA
    original_reference_id: PMID:27224062
    review:
      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.
      action: KEEP_AS_NON_CORE
      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.
      supported_by:
        - reference_id: PMID:27224062
          supporting_text: "ERC1 expression was retained at the basal body of ciliated cells"

  # ===== HDA ANNOTATION =====
  - term:
      id: GO:0045296
      label: cadherin binding
    evidence_type: HDA
    original_reference_id: PMID:25468996
    review:
      summary: >-
        ERC1 was identified as part of the E-cadherin interactome by quantitative
        proteomics (PMID:25468996). This is a high-throughput annotation.
      action: UNDECIDED
      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.
      supported_by:
        - reference_id: PMID:25468996
          supporting_text: E-cadherin interactome complexity and robustness
            resolved by quantitative proteomics.

  # ===== ISS ANNOTATIONS =====
  - term:
      id: GO:0002102
      label: podosome
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    review:
      summary: >-
        ERC1 localizes to the cortex of myotube podosomes, based on sequence
        similarity transfer from mouse ERC1 (Q99MI1). UniProt notes this
        localization by similarity.
      action: KEEP_AS_NON_CORE
      reason: >-
        Podosome localization is supported by similarity from mouse data. However,
        podosomes are a specialized context and not a core localization for ERC1.

  - term:
      id: GO:0005737
      label: cytoplasm
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    review:
      summary: >-
        Cytoplasmic localization transferred by sequence similarity. Redundant
        with IDA evidence from PMID:15218148 and IEA annotation.
      action: ACCEPT
      reason: >-
        Cytoplasmic localization is well-established for ERC1 from multiple
        sources. This ISS annotation is consistent with direct evidence.

  - term:
      id: GO:0030165
      label: PDZ domain binding
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    review:
      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).
      action: ACCEPT
      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.
      supported_by:
        - reference_id: PMID:12391317
          supporting_text: "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"

  - term:
      id: GO:0031267
      label: small GTPase binding
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    review:
      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.
      action: ACCEPT
      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.
      supported_by:
        - reference_id: PMID:12391317
          supporting_text: "both ubiquitous and brain-specific ERCs bind to Rab6, a GTP-binding protein involved in membrane traffic at the Golgi complex"

  - term:
      id: GO:0042147
      label: retrograde transport, endosome to Golgi
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    review:
      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.
      action: MARK_AS_OVER_ANNOTATED
      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.
      supported_by:
        - reference_id: PMID:12391317
          supporting_text: "both ubiquitous and brain-specific ERCs bind to Rab6, a GTP-binding protein involved in membrane traffic at the Golgi complex"

  - term:
      id: GO:0045202
      label: synapse
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    review:
      summary: >-
        ERC1 localizes to synapses, specifically to the presynaptic active zone.
        Brain-specific isoforms (ERC1b) are active zone components (PMID:12391317).
      action: ACCEPT
      reason: >-
        Synaptic localization is well-established for ERC1. This broader term
        is consistent with the more specific presynaptic active zone annotations.

  # ===== TAS ANNOTATION =====
  - term:
      id: GO:0042734
      label: presynaptic membrane
    evidence_type: TAS
    original_reference_id: PMID:12391317
    review:
      summary: >-
        ERC1b localizes to the presynaptic membrane/active zone as established
        by Wang et al. (2002) (PMID:12391317).
      action: ACCEPT
      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.
      supported_by:
        - reference_id: PMID:12391317
          supporting_text: "ERC1b is detectable only in brain, where it is both a cytosolic protein and an insoluble active zone component"

  # ===== MISSING ANNOTATIONS (NEW) =====
  - term:
      id: GO:0007252
      label: I-kappaB phosphorylation
    evidence_type: IDA
    original_reference_id: PMID:15218148
    review:
      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.
      action: NEW
      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.
      supported_by:
        - reference_id: PMID:15218148
          supporting_text: "ELKS likely functions by recruiting IkappaBalpha to the IKK complex and thus serves a regulatory function for IKK activation"

references:
  - id: GO_REF:0000024
    title: Manual transfer of experimentally-verified manual GO annotation data
      to orthologs by curator judgment of sequence similarity
    findings: []
  - id: GO_REF:0000033
    title: Annotation inferences using phylogenetic trees
    findings: []
  - id: GO_REF:0000043
    title: Gene Ontology annotation based on UniProtKB/Swiss-Prot keyword mapping
    findings: []
  - id: GO_REF:0000044
    title: Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular
      Location vocabulary mapping, accompanied by conservative changes to GO
      terms applied by UniProt
    findings: []
  - id: GO_REF:0000052
    title: Gene Ontology annotation based on curation of immunofluorescence data
    findings: []
  - id: GO_REF:0000117
    title: Electronic Gene Ontology annotations created by ARBA machine learning
      models
    findings: []
  - id: PMID:12391317
    title: 'A family of RIM-binding proteins regulated by alternative splicing: Implications
      for the genesis of synaptic active zones.'
    findings:
      - statement: >-
          ERC1 isoforms are alternatively spliced; ERC1a is ubiquitous and cytosolic,
          ERC1b is brain-specific and localizes to active zones. Both bind Rab6, but
          only ERC1b binds RIM.
        supporting_text: "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"
  - id: PMID:12923177
    title: Interaction of the ERC family of RIM-binding proteins with the
      liprin-alpha family of multidomain proteins.
    findings:
      - statement: >-
          ERC proteins directly interact with liprin-alpha family, and this
          interaction promotes presynaptic localization of liprin-alpha and
          active zone organization.
        supporting_text: "liprin-alpha directly interacts with the ERC (ELKS-Rab6-interacting protein-CAST) family of proteins"
  - id: PMID:15218148
    title: Activation of transcription factor NF-kappaB requires ELKS, an
      IkappaB kinase regulatory subunit.
    findings:
      - statement: >-
          ELKS/ERC1 is a regulatory subunit of the IKK complex required for
          NF-kappaB activation. It recruits IkappaBalpha to the IKK complex.
        supporting_text: "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"
  - id: PMID:15324660
    title: Proteomic, functional, and domain-based analysis of in vivo 14-3-3
      binding proteins involved in cytoskeletal regulation and cellular
      organization.
    findings: []
  - id: PMID:17353931
    title: Large-scale mapping of human protein-protein interactions by mass
      spectrometry.
    findings: []
  - id: PMID:25468996
    title: E-cadherin interactome complexity and robustness resolved by
      quantitative proteomics.
    findings: []
  - id: PMID:27224062
    title: SDCCAG8 Interacts with RAB Effector Proteins RABEP2 and ERC1 and Is
      Required for Hedgehog Signaling.
    findings:
      - statement: >-
          ERC1 localizes to centrosomes and ciliary basal bodies, and interacts
          with SDCCAG8 at the centrosome. This was the first demonstration of
          centriolar localization for ERC1.
        supporting_text: "RABEP2 and ERC1 localize to the centrioles of non-ciliated cells...ERC1 expression was retained at the basal body of ciliated cells"
  - id: PMID:28514442
    title: Architecture of the human interactome defines protein communities and
      disease networks.
    findings: []
  - id: PMID:33961781
    title: Dual proteome-scale networks reveal cell-specific remodeling of the
      human interactome.
    findings: []
  - id: PMID:35271311
    title: 'OpenCell: Endogenous tagging for the cartography of human cellular organization.'
    findings: []
  - id: PMID:36931259
    title: A central chaperone-like role for 14-3-3 proteins in human cells.
    findings: []

core_functions:
  - description: >-
      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.
    molecular_function:
      id: GO:0098882
      label: structural constituent of presynaptic active zone
    directly_involved_in:
      - id: GO:0048790
        label: maintenance of presynaptic active zone structure
    locations:
      - id: GO:0098831
        label: presynaptic active zone cytoplasmic component
    supported_by:
      - reference_id: PMID:12391317
        supporting_text: "ERC1b is detectable only in brain, where it is both a cytosolic protein and an insoluble active zone component"
      - reference_id: PMID:12923177
        supporting_text: "liprin-alpha directly interacts with the ERC (ELKS-Rab6-interacting protein-CAST) family of proteins"

  - description: >-
      Rab6 effector and vesicle capture scaffold at plasma membrane-associated
      platforms (PMAPs). ERC1 binds active Rab6B via its C-terminal RBD domain
      (residues 849-922, ~8 uM affinity) and captures Rab6-positive secretory
      vesicles at cortical platforms containing LL5-beta and CLASPs, promoting
      directed exocytosis. This function operates in both neuronal (active zone)
      and non-neuronal (PMAP) contexts, including insulin secretion hot spots
      in pancreatic beta cells.
    molecular_function:
      id: GO:0031267
      label: small GTPase binding
    directly_involved_in:
      - id: GO:0015031
        label: protein transport
    locations:
      - id: GO:0005737
        label: cytoplasm
      - id: GO:0000139
        label: Golgi membrane
    supported_by:
      - reference_id: PMID:12391317
        supporting_text: "both ubiquitous and brain-specific ERCs bind to Rab6, a GTP-binding protein involved in membrane traffic at the Golgi complex"

  - description: >-
      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.
    molecular_function:
      id: GO:0030674
      label: protein-macromolecule adaptor activity
    directly_involved_in:
      - id: GO:0043123
        label: positive regulation of canonical NF-kappaB signal transduction
    locations:
      - id: GO:0005737
        label: cytoplasm
    in_complex:
      id: GO:0008385
      label: IkappaB kinase complex
    supported_by:
      - reference_id: PMID:15218148
        supporting_text: "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"