id: Q9Y3B6
gene_symbol: EMC9
product_type: PROTEIN
status: COMPLETE
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: EMC9 (ER membrane protein complex subunit 9; also FAM158A) is a 208 aa cytosolic, peripheral subunit of the ER membrane protein complex (EMC), associated with the cytoplasmic face of the ER membrane. It belongs to the EMC8/EMC9 family and contains an MPN (Mpr1/Pad1 N-terminal) domain that is degenerate and lacks the catalytic residues of active JAMM/MPN metalloproteases, so EMC9 is not predicted to have intrinsic enzymatic activity. EMC9 and its paralog EMC8 are mutually exclusive subunits of the EMC, defining alternative complex variants; EMC9 docks into the complex primarily through binding to EMC2. The EMC is a conserved transmembrane-domain insertase and membrane-protein chaperone that mediates energy-independent insertion of newly synthesized membrane proteins into the ER membrane, including post-translational insertion of tail-anchored proteins and cotranslational insertion and topogenesis of multipass membrane proteins. As a peripheral, non-catalytic subunit, EMC9 participates in these processes through complex membership rather than direct catalysis; the membrane insertase activity resides in the EMC3/EMC6 core. EMC9 is broadly expressed and remains relatively weakly characterized.
existing_annotations:
- term:
    id: GO:0032977
    label: membrane insertase activity
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: contributes_to
  review:
    summary: Phylogenetic propagation of membrane insertase activity across the EMC8/EMC9 family with the contributes_to qualifier. EMC9 is a peripheral, non-catalytic subunit and an EMC8 paralog; the insertase activity is a property of the EMC core (EMC3/EMC6), to which EMC9 contributes only via complex membership.
    action: KEEP_AS_NON_CORE
    reason: contributes_to is appropriate at the complex level, but this is not EMC9's own enzymatic core function; EMC8 and EMC9 are interchangeable, so neither is individually required for the catalytic insertase reaction.
    supported_by:
    - reference_id: file:human/EMC9/EMC9-uniprot.txt
      supporting_text: energy-independent insertion into endoplasmic
- term:
    id: GO:0045050
    label: protein insertion into ER membrane by stop-transfer membrane-anchor sequence
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: Phylogenetic propagation of the EMC stop-transfer insertion process. A genuine EMC whole-complex process in which EMC9 participates as a subunit.
    action: KEEP_AS_NON_CORE
    reason: Correct EMC process but complex-level; EMC9's contribution is via membership, and the EMC8/EMC9 paralogs are interchangeable.
    supported_by:
    - reference_id: file:human/EMC9/EMC9-uniprot.txt
      supporting_text: stop-transfer membrane-anchor sequences become ER membrane spanning
- term:
    id: GO:0071816
    label: tail-anchored membrane protein insertion into ER membrane
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: Phylogenetic propagation of the EMC tail-anchored protein insertion process. A genuine EMC whole-complex process in which EMC9 participates as a subunit.
    action: KEEP_AS_NON_CORE
    reason: Correct EMC process but complex-level; EMC9's contribution is via membership.
    supported_by:
    - reference_id: file:human/EMC9/EMC9-uniprot.txt
      supporting_text: post-translational insertion of tail-
- term:
    id: GO:0072546
    label: EMC complex
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: part_of
  review:
    summary: EMC9 is a constitutive (variant) subunit of the ER membrane protein complex; phylogenetic assignment is consistent with direct experimental and structural evidence. Core structural identity of EMC9.
    action: ACCEPT
    reason: EMC complex membership is the core cellular-component identity of EMC9; supported by IDA, the EMC9-EMC2 crystal structure, and cryo-EM of the EMC.
    supported_by:
    - reference_id: file:human/EMC9/EMC9-uniprot.txt
      supporting_text: Component of the ER membrane protein complex (EMC)
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: Electronic transfer of the ER membrane subcellular location from UniProt; EMC9 is a peripheral protein on the cytoplasmic side of the ER membrane. Core compartment.
    action: ACCEPT
    reason: Correct core location for an EMC subunit; consistent with the peripheral/cytoplasmic-side localization.
    supported_by:
    - reference_id: file:human/EMC9/EMC9-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Endoplasmic reticulum membrane'
- term:
    id: GO:0072546
    label: EMC complex
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: part_of
  review:
    summary: InterPro-based electronic assignment of EMC complex membership, consistent with the experimental IDA annotation. Core structural identity.
    action: ACCEPT
    reason: Correct core structural identity; redundant with IDA/IBA evidence.
    supported_by:
    - reference_id: file:human/EMC9/EMC9-uniprot.txt
      supporting_text: Component of the ER membrane protein complex (EMC)
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:16189514
  qualifier: enables
  review:
    summary: High-throughput proteome-scale interaction capture. EMC9's most informative partner is EMC2 (it docks into the complex via EMC2), but bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: Real but the bare protein binding term is uninformative per curation guidelines; the EMC complex membership term captures the informative content.
    supported_by:
    - reference_id: file:human/EMC9/EMC9-uniprot.txt
      supporting_text: 'Q9Y3B6; Q15006: EMC2'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:22119785
  qualifier: enables
  review:
    summary: Interaction capture from the foundational ERAD-network mapping study that first defined the EMC and placed FAM158A/EMC9 in it. Genuine EMC partnership; bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: Real EMC partner interaction but the bare term is uninformative; EMC membership captures the content.
    supported_by:
    - reference_id: file:human/EMC9/EMC9-uniprot.txt
      supporting_text: 'Q9Y3B6; Q15006: EMC2'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:25416956
  qualifier: enables
  review:
    summary: Proteome-scale interactome map capture. Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: High-throughput interaction; bare protein binding is uninformative and not core.
    supported_by:
    - reference_id: file:human/EMC9/EMC9-uniprot.txt
      supporting_text: 'Q9Y3B6; Q15006: EMC2'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:28514442
  qualifier: enables
  review:
    summary: BioPlex protein-community interactome capture. Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: High-throughput interaction; bare protein binding is uninformative and not core.
    supported_by:
    - reference_id: file:human/EMC9/EMC9-uniprot.txt
      supporting_text: 'Q9Y3B6; Q15006: EMC2'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:32296183
  qualifier: enables
  review:
    summary: Binary (HuRI) interactome capture, including an interaction with an SCN5A isoform, a plausible EMC client. Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: High-throughput interaction partly reflecting client engagement; the bare term is uninformative and not core.
    supported_by:
    - reference_id: file:human/EMC9/EMC9-uniprot.txt
      supporting_text: 'Q9Y3B6; Q14524-3: SCN5A'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:32439656
  qualifier: enables
  review:
    summary: Interaction evidence associated with the cryo-EM structural study of the human EMC, reflecting intra-complex partnerships (notably EMC2). Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: Real intra-complex interaction; the EMC complex membership term captures the informative content.
    supported_by:
    - reference_id: file:human/EMC9/EMC9-uniprot.txt
      supporting_text: 'Q9Y3B6; Q15006: EMC2'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:33961781
  qualifier: enables
  review:
    summary: BioPlex affinity-MS interactome capture. Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: High-throughput interaction; bare protein binding is uninformative and not core.
    supported_by:
    - reference_id: file:human/EMC9/EMC9-uniprot.txt
      supporting_text: 'Q9Y3B6; Q15006: EMC2'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:35271311
  qualifier: enables
  review:
    summary: OpenCell endogenous-tagging interactome capture. Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: High-throughput interaction; bare protein binding is uninformative and not core.
    supported_by:
    - reference_id: file:human/EMC9/EMC9-uniprot.txt
      supporting_text: 'Q9Y3B6; Q15006: EMC2'
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: NAS
  original_reference_id: PMID:29242231
  qualifier: located_in
  review:
    summary: NAS annotation of ER membrane localization for the EMC, consistent with EMC9's peripheral/cytoplasmic-side ER membrane localization. Core compartment.
    action: ACCEPT
    reason: Correct core location; consistent with experimental evidence.
    supported_by:
    - reference_id: file:human/EMC9/EMC9-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Endoplasmic reticulum membrane'
- term:
    id: GO:0045050
    label: protein insertion into ER membrane by stop-transfer membrane-anchor sequence
  evidence_type: IDA
  original_reference_id: PMID:29242231
  qualifier: involved_in
  review:
    summary: The EMC inserts transmembrane domains including stop-transfer membrane-anchor sequences; EMC9 participates as a (variant) subunit. A genuine EMC whole-complex process.
    action: KEEP_AS_NON_CORE
    reason: Correct EMC process but complex-level; EMC9 is a peripheral subunit contributing via membership rather than catalysis.
    supported_by:
    - reference_id: file:human/EMC9/EMC9-uniprot.txt
      supporting_text: stop-transfer membrane-anchor sequences become ER membrane spanning
- term:
    id: GO:0071816
    label: tail-anchored membrane protein insertion into ER membrane
  evidence_type: IDA
  original_reference_id: PMID:29242231
  qualifier: involved_in
  review:
    summary: The EMC mediates post-translational insertion of tail-anchored proteins; EMC9 participates as a subunit. A genuine EMC whole-complex process.
    action: KEEP_AS_NON_CORE
    reason: Correct EMC process but complex-level; EMC9's contribution is via membership.
    supported_by:
    - reference_id: file:human/EMC9/EMC9-uniprot.txt
      supporting_text: post-translational insertion of tail-
- term:
    id: GO:0032977
    label: membrane insertase activity
  evidence_type: IMP
  original_reference_id: PMID:29809151
  qualifier: contributes_to
  review:
    summary: IMP evidence that EMC subunit depletion impairs membrane insertion; EMC9 contributes to the complex-level insertase activity but is not the catalytic subunit.
    action: KEEP_AS_NON_CORE
    reason: contributes_to is appropriate at complex level; not EMC9's standalone enzymatic core MF.
    supported_by:
    - reference_id: file:human/EMC9/EMC9-uniprot.txt
      supporting_text: energy-independent insertion into endoplasmic
- term:
    id: GO:0032977
    label: membrane insertase activity
  evidence_type: IMP
  original_reference_id: PMID:30415835
  qualifier: contributes_to
  review:
    summary: IMP evidence (topogenesis study) supporting the EMC's membrane insertase activity, to which EMC9 contributes as a subunit.
    action: KEEP_AS_NON_CORE
    reason: contributes_to is appropriate at complex level; not EMC9's standalone enzymatic core MF.
    supported_by:
    - reference_id: file:human/EMC9/EMC9-uniprot.txt
      supporting_text: energy-independent insertion into endoplasmic
- term:
    id: GO:0045050
    label: protein insertion into ER membrane by stop-transfer membrane-anchor sequence
  evidence_type: IMP
  original_reference_id: PMID:29809151
  qualifier: involved_in
  review:
    summary: The EMC is required for cotranslational insertion of multipass proteins in which stop-transfer membrane-anchor sequences become membrane-spanning helices; EMC9 participates as a subunit.
    action: KEEP_AS_NON_CORE
    reason: Correct EMC process but complex-level; EMC9's contribution is via membership.
    supported_by:
    - reference_id: file:human/EMC9/EMC9-uniprot.txt
      supporting_text: stop-transfer membrane-anchor sequences become ER membrane spanning
- term:
    id: GO:0045050
    label: protein insertion into ER membrane by stop-transfer membrane-anchor sequence
  evidence_type: IMP
  original_reference_id: PMID:30415835
  qualifier: involved_in
  review:
    summary: IMP (topogenesis study) supporting the EMC's role in insertion of stop-transfer membrane-anchor sequences; EMC9 participates as a subunit.
    action: KEEP_AS_NON_CORE
    reason: Correct EMC process but complex-level; EMC9's contribution is via membership.
    supported_by:
    - reference_id: file:human/EMC9/EMC9-uniprot.txt
      supporting_text: stop-transfer membrane-anchor sequences become ER membrane spanning
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IDA
  original_reference_id: PMID:22119785
  qualifier: located_in
  review:
    summary: Direct evidence that EMC9 is on the cytoplasmic side of the ER membrane; consistent with its peripheral membrane localization. The more informative compartment is the ER membrane.
    action: KEEP_AS_NON_CORE
    reason: Accurate (EMC9 is cytoplasmic-side peripheral) but less specific than the ER membrane localization that captures its functional context.
    supported_by:
    - reference_id: file:human/EMC9/EMC9-uniprot.txt
      supporting_text: Cytoplasmic side
- term:
    id: GO:0072546
    label: EMC complex
  evidence_type: IDA
  original_reference_id: PMID:22119785
  qualifier: part_of
  review:
    summary: Direct experimental identification of FAM158A/EMC9 in the EMC by the foundational ERAD-network mapping study. Core structural identity.
    action: ACCEPT
    reason: Core EMC membership; directly demonstrated and the best-supported EMC9-specific assertion.
    supported_by:
    - reference_id: file:human/EMC9/EMC9-uniprot.txt
      supporting_text: Component of the ER membrane protein complex (EMC)
core_functions:
- description: Cytosolic, peripheral (variant) subunit of the ER membrane protein complex (EMC), associated with the cytoplasmic face of the ER membrane and docking into the complex via EMC2; mutually exclusive with its paralog EMC8.
  molecular_function:
    id: GO:0005198
    label: structural molecule activity
  in_complex:
    id: GO:0072546
    label: EMC complex
  locations:
  - id: GO:0005789
    label: endoplasmic reticulum membrane
  supported_by:
  - reference_id: file:human/EMC9/EMC9-uniprot.txt
    supporting_text: Component of the ER membrane protein complex (EMC)
  - reference_id: file:human/EMC9/EMC9-uniprot.txt
    supporting_text: EMC8 and EMC9 are
proposed_new_terms: []
references:
- id: GO_REF:0000002
  title: Gene Ontology annotation through association of InterPro records with GO terms
  findings: []
- id: GO_REF:0000033
  title: Annotation inferences using phylogenetic trees
  findings: []
- id: GO_REF:0000044
  title: Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location vocabulary mapping, accompanied by conservative changes to GO terms applied by UniProt
  findings: []
- id: PMID:16189514
  title: Towards a proteome-scale map of the human protein-protein interaction network.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: Proteome-scale interactome; source of an IPI protein-binding annotation.
- id: PMID:22119785
  title: Defining human ERAD networks through an integrative mapping strategy.
  findings:
  - statement: Affinity-MS ERAD-network mapping that first identified the EMC (including FAM158A/EMC9) and placed it on the cytoplasmic side of the ER membrane.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Foundational identification of the human EMC; source of EMC membership and cytoplasmic-side ER membrane localization for EMC9.
- id: PMID:25416956
  title: A proteome-scale map of the human interactome network.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: Proteome-scale interactome; source of an IPI protein-binding annotation.
- id: PMID:28514442
  title: Architecture of the human interactome defines protein communities and disease networks.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: BioPlex interactome; source of an IPI protein-binding annotation.
- id: PMID:29242231
  title: The ER membrane protein complex is a transmembrane domain insertase.
  findings:
  - statement: EMC is a transmembrane domain insertase mediating tail-anchored and stop-transfer insertion.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: Establishes the insertase function of the EMC; EMC9 participates as a variant subunit.
- id: PMID:29809151
  title: The ER membrane protein complex interacts cotranslationally to enable biogenesis of multipass membrane proteins.
  findings:
  - statement: The EMC engages multipass membrane protein clients cotranslationally to enable their biogenesis.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: Cotranslational multipass biogenesis role of the EMC.
- id: PMID:30415835
  title: EMC Is Required to Initiate Accurate Membrane Protein Topogenesis.
  findings:
  - statement: The EMC sets the N-exo topology of the first TMD of multipass proteins.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: Topogenesis/orientation role of the EMC.
- id: PMID:32296183
  title: A reference map of the human binary protein interactome.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: HuRI binary interactome; source of an IPI protein-binding annotation (SCN5A client).
- id: PMID:32439656
  title: Structural basis for membrane insertion by the human ER membrane protein complex.
  findings:
  - statement: Cryo-EM structure of the human EMC, including the EMC9 variant.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: Structural basis for the EMC; abstract-only in cache.
- id: PMID:33961781
  title: Dual proteome-scale networks reveal cell-specific remodeling of the human interactome.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: BioPlex affinity-MS interactome; source of an IPI protein-binding annotation.
- id: PMID:35271311
  title: 'OpenCell: Endogenous tagging for the cartography of human cellular organization.'
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: OpenCell interactome/localization; source of an IPI protein-binding annotation.
- id: PMID:32459176
  title: The architecture of EMC reveals a path for membrane protein insertion.
  findings:
  - statement: Cryo-EM and crystallography of the human EMC; EMC8 and EMC9 are mutually exclusive subunits and EMC9 binds EMC2.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: PubMed-verified (eLife 2020, PMID:32459176). Source of the EMC8/EMC9 mutual exclusivity and the EMC9-EMC2 interaction; not in publication cache (cited from UniProt).
- id: PMID:37318954
  title: Expanding EMC foldopathies, topogenesis deficits alter the neural crest.
  findings:
  - statement: Damaging EMC9 (and EMC10) variants are reported in 18 individuals from 10 families with congenital anomalies; CRISPR depletion of emc9 in Xenopus tropicalis reduced neural crest marker (sox10) expression and produced craniofacial and neuromuscular phenotypes, and decreased the WNT receptor Fzd7 with marked reduction of nuclear beta-catenin, implicating EMC9 in membrane-protein topogenesis required for WNT-dependent development.
    reference_section_type: RESULTS
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: PubMed-verified (genesis 2023, PMID:37318954). Most EMC9-specific functional/disease evidence available, developmental "foldopathy" with WNT-pathway readout; supports non-redundant developmental importance of EMC9.
- id: PMID:32332093
  title: Squaring the EMC - how promoting membrane protein biogenesis impacts cellular functions and organismal homeostasis.
  findings:
  - statement: Review placing EMC2, EMC8, and EMC9 as the cytosolic (non-transmembrane, peripheral) subunits forming the cytoplasmic interface of the ER-resident EMC; EMC9 (~208 aa) is classified among peripheral, non-core subunits.
    reference_section_type: LITERATURE_REVIEW
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: PubMed-verified (J Cell Sci 2020, PMID:32332093). Review supporting EMC9's cytosolic/peripheral localization and EMC8/EMC9 paralog framing already in the review.
- id: PMID:35287476
  title: The Function, Structure, and Origins of the ER Membrane Protein Complex.
  findings:
  - statement: Authoritative review placing EMC2, EMC8, and EMC9 as cytosolic subunits, with the EMC8/EMC9-containing cytosolic cradle likely engaging membrane-protein clients before insertion/folding.
    reference_section_type: LITERATURE_REVIEW
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: PubMed-verified (Annu Rev Biochem 2022, PMID:35287476). Review supporting EMC9's cytosolic placement and client-engagement role of the cytosolic module.
- id: PMID:37196677
  title: "EMC chaperone-Ca(V) structure reveals an ion channel assembly intermediate."
  findings:
  - statement: Cryo-EM of human EMC bound to a CaV1.2-CaVbeta3 assembly intermediate shows the cytosolic module (EMC2 plus the EMC8/EMC9 slot) can directly bind clients at a "Cyto dock"; EMC8 is directly visualized while EMC9 involvement is inferred via paralogous alternative complex composition.
    reference_section_type: RESULTS
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: PubMed-verified (Nature 2023, PMID:37196677). Demonstrates client-binding by the cytosolic EMC2-EMC8/9 module; EMC9 role inferred by paralogy (EMC8 is the subunit resolved in this structure), so relevance to EMC9 specifically is indirect.
suggested_questions:
- question: Do the EMC8- and EMC9-containing EMC variants differ in client specificity, tissue distribution, or regulation, and what determines which paralog is incorporated?
- question: Does the degenerate MPN domain of EMC9 retain any binding or regulatory activity, or is it purely a structural scaffold for docking onto EMC2?
suggested_experiments:
- description: Compare client repertoires and insertion efficiencies of EMC8-only versus EMC9-only complexes using paralog-specific knockouts with quantitative membrane proteomics and reconstituted insertion assays.
- description: Solve or model the EMC9 MPN domain in the holo-complex and test by mutagenesis whether the EMC9-EMC2 interface is required for complex assembly and stability.