id: O43402
gene_symbol: EMC8
product_type: PROTEIN
status: COMPLETE
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: 'EMC8 (ER membrane protein complex subunit 8; also known as C16orf2/C16orf4, COX4NB/NOC4 "Neighbor of COX4", FAM158B) is a small (210 aa) cytosolic, peripherally membrane-associated subunit of the endoplasmic reticulum membrane protein complex (EMC). The EMC is a conserved, nine-subunit ER transmembrane-domain insertase and membrane-protein chaperone that mediates energy-independent insertion of newly synthesized membrane proteins into the ER membrane, with a preference for transmembrane domains that are weakly hydrophobic or carry destabilizing charged/aromatic residues. The complex acts both co-translationally on multipass membrane proteins (where stop-transfer/membrane-anchor sequences become spanning helices, controlling N-exo topology of substrates such as G protein-coupled receptors) and post-translationally on tail-anchored proteins. Within EMC, EMC8 lies on the cytoplasmic face of the complex and is a non-catalytic accessory subunit; it contains an MPN domain (a JAMM/MPN-related fold) but lacks the catalytic metalloprotease residues, and the substrate-insertion vestibule is provided by the transmembrane subunits EMC3/EMC6 rather than by EMC8. EMC8 and its paralog EMC9 are mutually exclusive subunits that occupy the same position, defining alternative EMC variants. EMC8 docks onto the EMC2 scaffold subunit, its principal and well-documented protein interaction. EMC8 is broadly expressed across human tissues.'
alternative_products:
- name: '1'
  id: O43402-1
- name: '2'
  id: O43402-2
  sequence_note: VSP_045089
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 (IBA) assignment of membrane insertase activity with the contributes_to qualifier, reflecting EMC8 participation in the EMC insertase complex rather than an intrinsic enzymatic activity of EMC8 itself.
    action: KEEP_AS_NON_CORE
    reason: Correct use of contributes_to for a non-catalytic subunit of the EMC insertase. EMC8 is a cytosolic accessory subunit and is not the catalytic insertase (the insertion vestibule is formed by EMC3/EMC6), so this complex-level MF is retained but not as the standalone core function. The core descriptor for EMC8 is EMC complex membership plus ER membrane localization.
    supported_by:
    - reference_id: file:human/EMC8/EMC8-uniprot.txt
      supporting_text: enables the 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 assignment of the EMC role in cotranslational insertion of multipass membrane proteins via stop-transfer/membrane-anchor sequences; a process EMC8 participates in as part of the complex.
    action: ACCEPT
    reason: Consistent with the experimentally supported EMC function; the complex mediates cotranslational insertion of multipass proteins in which stop-transfer anchors become membrane-spanning helices. This is a complex-level process EMC8 is involved in.
    supported_by:
    - reference_id: file:human/EMC8/EMC8-uniprot.txt
      supporting_text: cotranslational insertion of multi-pass membrane proteins in which
- 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 assignment of the EMC role in post-translational insertion of tail-anchored proteins; EMC8 participates as part of the complex.
    action: ACCEPT
    reason: Consistent with experimental evidence that EMC is required for post-translational insertion of tail-anchored proteins into the ER membrane.
    supported_by:
    - reference_id: file:human/EMC8/EMC8-uniprot.txt
      supporting_text: post-translational insertion of tail-anchored/TA proteins in
- term:
    id: GO:0072546
    label: EMC complex
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: part_of
  review:
    summary: Phylogenetic assignment of EMC complex membership, the defining and core cellular-component association for EMC8.
    action: ACCEPT
    reason: Core localization/membership for EMC8; directly demonstrated experimentally (IDA PMID:22119785; IPI PMID:32439656) and conserved across the EMC8/EMC9 family.
    supported_by:
    - reference_id: file:human/EMC8/EMC8-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 localization from the UniProt subcellular location, consistent with EMC8 being a peripheral, cytoplasmic-side subunit of the ER-resident EMC.
    action: ACCEPT
    reason: Correct core compartment; EMC8 is a peripheral membrane protein at the ER membrane. Redundant with EXP/NAS ER membrane annotations.
    supported_by:
    - reference_id: file:human/EMC8/EMC8-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 (IPR005366, EMC8/9 family) electronic assignment to the EMC complex, consistent with the experimental membership annotation.
    action: ACCEPT
    reason: Correct core membership; redundant with IDA/IPI/IBA evidence for EMC complex membership.
    supported_by:
    - reference_id: file:human/EMC8/EMC8-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 yeast two-hybrid human interactome capturing the EMC8-EMC2 interaction (WITH/FROM UniProtKB:Q15006). Bare protein binding is uninformative, though the EMC2 partner is the scaffold EMC8 docks onto within the complex.
    action: KEEP_AS_NON_CORE
    reason: Records a real interaction with EMC2 (the EMC scaffold) but bare protein binding does not convey function; per guidelines not elevated to core. The functional content is captured by EMC complex membership.
    supported_by:
    - reference_id: file:human/EMC8/EMC8-uniprot.txt
      supporting_text: 'O43402; Q15006: EMC2; NbExp=17'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:22119785
  qualifier: enables
  review:
    summary: EMC8-EMC2 interaction (WITH/FROM UniProtKB:Q15006) from the integrative ERAD/EMC mapping study that originally placed EMC8 (as COX4NB) in the mammalian EMC. Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: Real, biologically meaningful interaction with the EMC2 scaffold, but the bare MF term is uninformative; the membership is better captured by GO:0072546.
    supported_by:
    - reference_id: file:human/EMC8/EMC8-uniprot.txt
      supporting_text: 'O43402; Q15006: EMC2; NbExp=17'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:26496610
  qualifier: enables
  review:
    summary: EMC8-EMC2 interaction (WITH/FROM UniProtKB:Q15006) from a quantitative stoichiometry-resolved interactome. Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: Genuine EMC2 interaction from a high-throughput study, but bare protein binding is uninformative; intra-EMC contact captured by complex membership.
    supported_by:
    - reference_id: file:human/EMC8/EMC8-uniprot.txt
      supporting_text: 'O43402; Q15006: EMC2; NbExp=17'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:28514442
  qualifier: enables
  review:
    summary: EMC8-EMC2 interaction (WITH/FROM UniProtKB:Q15006) from the BioPlex interactome/community analysis. Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: Real EMC2 interaction from a high-throughput AP-MS network, but bare protein binding is uninformative; not elevated to core.
    supported_by:
    - reference_id: file:human/EMC8/EMC8-uniprot.txt
      supporting_text: 'O43402; Q15006: EMC2; NbExp=17'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:30021884
  qualifier: enables
  review:
    summary: EMC8-EMC2 interaction (WITH/FROM UniProtKB:Q15006) entered into IntAct from a crosslinking-MS study. The paper title concerns histone interaction landscapes, an unexpected source, but the curated datapoint records an EMC8-EMC2 contact.
    action: KEEP_AS_NON_CORE
    reason: Curator-entered experimental IPI to the known EMC2 partner; per guidelines an experimental IPI is not removed merely because the abstract foregrounds a different topic. Bare protein binding remains uninformative, so kept as non-core.
    supported_by:
    - reference_id: file:human/EMC8/EMC8-uniprot.txt
      supporting_text: 'O43402; Q15006: EMC2; NbExp=17'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:32296183
  qualifier: enables
  review:
    summary: EMC8-EMC2 interaction (WITH/FROM UniProtKB:Q15006) from the HuRI reference binary interactome. Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: Genuine binary EMC2 interaction, but bare protein binding is uninformative; complex membership captures the functional content.
    supported_by:
    - reference_id: file:human/EMC8/EMC8-uniprot.txt
      supporting_text: 'O43402; Q15006: EMC2; NbExp=17'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:32439656
  qualifier: enables
  review:
    summary: EMC8-EMC2 interaction (WITH/FROM UniProtKB:Q15006) consistent with the cryo-EM structure of the human EMC, which resolves EMC8 contacting the EMC2 scaffold. Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: Structurally corroborated EMC2 interaction, but bare protein binding is uninformative; the structural membership is captured by GO:0072546 EMC complex.
    supported_by:
    - reference_id: file:human/EMC8/EMC8-uniprot.txt
      supporting_text: 'O43402; Q15006: EMC2; NbExp=17'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:33961781
  qualifier: enables
  review:
    summary: EMC8-EMC2 interaction (WITH/FROM UniProtKB:Q15006) from BioPlex 3 dual proteome-scale networks. Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: Real EMC2 interaction from a large AP-MS network, but bare protein binding is uninformative; not elevated to core.
    supported_by:
    - reference_id: file:human/EMC8/EMC8-uniprot.txt
      supporting_text: 'O43402; Q15006: EMC2; NbExp=17'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:35271311
  qualifier: enables
  review:
    summary: EMC8-EMC2 interaction (WITH/FROM UniProtKB:Q15006) from OpenCell endogenous-tagging interactome/localization. Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: Genuine endogenous EMC2 interaction, but bare protein binding is uninformative; the functional content is captured by EMC complex membership.
    supported_by:
    - reference_id: file:human/EMC8/EMC8-uniprot.txt
      supporting_text: 'O43402; Q15006: EMC2; NbExp=17'
- term:
    id: GO:0005783
    label: endoplasmic reticulum
  evidence_type: IDA
  original_reference_id: GO_REF:0000052
  qualifier: located_in
  review:
    summary: Direct immunofluorescence (HPA) evidence for ER localization, consistent with EMC8 being a subunit of the ER-resident EMC.
    action: ACCEPT
    reason: Correct compartment; the more specific ER membrane (GO:0005789) better captures the peripheral, cytoplasmic-side association of EMC8.
    supported_by:
    - reference_id: file:human/EMC8/EMC8-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Endoplasmic reticulum membrane'
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: NAS
  original_reference_id: PMID:29242231
  qualifier: located_in
  review:
    summary: ComplexPortal (NAS) assertion of EMC8 ER membrane localization, drawn from the EMC insertase characterization. Core compartment for EMC8.
    action: ACCEPT
    reason: Correct core compartment; EMC8 is a peripheral membrane protein on the cytoplasmic side of the ER membrane. Consistent with EXP/IEA ER membrane annotations.
    supported_by:
    - reference_id: file:human/EMC8/EMC8-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: ComplexPortal IDA for the EMC role in cotranslational insertion of multipass proteins via stop-transfer anchors; EMC8 participates as part of the complex.
    action: ACCEPT
    reason: Consistent with experimentally demonstrated EMC insertase function; a complex-level process EMC8 is involved in.
    supported_by:
    - reference_id: file:human/EMC8/EMC8-uniprot.txt
      supporting_text: cotranslational insertion of multi-pass membrane proteins in which
- 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: ComplexPortal IDA for the EMC role in post-translational insertion of tail-anchored proteins, the function for which Guna et al. demonstrated EMC is necessary and sufficient. EMC8 participates as part of the complex.
    action: ACCEPT
    reason: Directly supported by the reconstitution evidence that EMC inserts tail-anchored substrates; a complex-level process EMC8 is involved in.
    supported_by:
    - reference_id: file:human/EMC8/EMC8-uniprot.txt
      supporting_text: post-translational insertion of tail-anchored/TA proteins in
- term:
    id: GO:0072546
    label: EMC complex
  evidence_type: IPI
  original_reference_id: PMID:32439656
  qualifier: part_of
  review:
    summary: ComplexPortal IPI placing EMC8 in the EMC, corroborated by the cryo-EM structure of the human nine-subunit complex. Core membership.
    action: ACCEPT
    reason: Core, structurally demonstrated EMC complex membership; EMC8 (chain H) is resolved in the human EMC structures.
    supported_by:
    - reference_id: file:human/EMC8/EMC8-uniprot.txt
      supporting_text: ComplexPortal; CPX-5848; Endoplasmic reticulum membrane complex, EMC8 variant.
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: EXP
  original_reference_id: PMID:22119785
  qualifier: located_in
  review:
    summary: Experimental localization of EMC8 (identified as COX4NB) to the ER membrane in the integrative ERAD/EMC mapping study. Core compartment.
    action: ACCEPT
    reason: Core compartment supported by direct experimental evidence; EMC8 associates peripherally with the ER membrane as part of EMC.
    supported_by:
    - reference_id: PMID:22119785
      supporting_text: we identified 5 additional HCIPs (TTC35, TMEM32/MMGT1, TMEM85, C15orf24 and COX4NB)
- term:
    id: GO:0032977
    label: membrane insertase activity
  evidence_type: IMP
  original_reference_id: PMID:29809151
  qualifier: contributes_to
  review:
    summary: IMP (loss-of-function) evidence that EMC subunits contribute to the membrane insertase activity of the complex, assigned to EMC8 with the contributes_to qualifier. The full text (subunit perturbation in cotranslational multipass biogenesis) was read by the curator.
    action: KEEP_AS_NON_CORE
    reason: Appropriate contributes_to assignment for a non-catalytic accessory subunit of the EMC insertase. EMC8 is not itself catalytic (the EMC3/EMC6 vestibule performs insertion), so this complex-level MF is retained but not as the standalone core function. Not removed, since contributes_to is the intended qualifier for subunit contributions to a complex activity.
    supported_by:
    - reference_id: file:human/EMC8/EMC8-uniprot.txt
      supporting_text: enables the 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 (EMC knockout/depletion in GPCR topogenesis) that the EMC has membrane insertase activity, assigned to EMC8 with contributes_to. Full text read by the curator.
    action: KEEP_AS_NON_CORE
    reason: Correct contributes_to assignment for a non-catalytic accessory subunit; the catalytic insertase activity is a property of the complex, not of EMC8 alone. Kept but not core for the individual subunit.
    supported_by:
    - reference_id: file:human/EMC8/EMC8-uniprot.txt
      supporting_text: the topology of multi-pass
- 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: IMP evidence that EMC (including EMC8) is required for cotranslational insertion of multipass membrane proteins via stop-transfer anchors.
    action: ACCEPT
    reason: Consistent with the experimentally supported EMC function; loss of EMC subunits impairs cotranslational multipass insertion. A complex-level process EMC8 is involved in.
    supported_by:
    - reference_id: file:human/EMC8/EMC8-uniprot.txt
      supporting_text: cotranslational insertion of multi-pass membrane proteins in which
- 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 evidence (EMC knockout impairs accurate GPCR/multipass topogenesis) supporting the EMC role in cotranslational insertion via stop-transfer anchors; EMC8 participates as part of the complex.
    action: ACCEPT
    reason: Consistent with experimental topogenesis evidence; EMC mediates cotranslational insertion that sets multipass topology. A complex-level process EMC8 is involved in.
    supported_by:
    - reference_id: file:human/EMC8/EMC8-uniprot.txt
      supporting_text: the proper cotranslational insertion of N-terminal
- term:
    id: GO:0016020
    label: membrane
  evidence_type: HDA
  original_reference_id: PMID:19946888
  qualifier: located_in
  review:
    summary: High-throughput membrane-proteome (NK-cell) MS dataset assigning generic membrane localization. Correct but a generic parent of the ER membrane localization.
    action: KEEP_AS_NON_CORE
    reason: Accurate but low-information; the specific ER membrane (GO:0005789) better captures the localization of EMC8.
    supported_by:
    - reference_id: file:human/EMC8/EMC8-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Endoplasmic reticulum membrane'
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IDA
  original_reference_id: PMID:22119785
  qualifier: located_in
  review:
    summary: Direct evidence consistent with EMC8 being on the cytoplasmic side of the ER membrane; cytoplasm is a correct but less specific compartment than ER membrane.
    action: KEEP_AS_NON_CORE
    reason: Correct (EMC8 is a peripheral, cytoplasmic-side subunit) but generic; the ER membrane localization and EMC complex membership are the informative core terms.
    supported_by:
    - reference_id: file:human/EMC8/EMC8-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 EMC8 (as COX4NB) as a component of the mammalian EMC; the foundational evidence for the core complex membership of EMC8.
    action: ACCEPT
    reason: Core, directly demonstrated EMC complex membership; this is the defining cellular-component association for EMC8.
    supported_by:
    - reference_id: PMID:22119785
      supporting_text: we identified 5 additional HCIPs (TTC35, TMEM32/MMGT1, TMEM85, C15orf24 and COX4NB)
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: GO_REF:0000052
  title: Gene Ontology annotation based on curation of immunofluorescence data
  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: High-throughput Y2H interactome; source of an EMC8-EMC2 protein binding IPI. Not informative about the molecular function of EMC8 beyond complex membership.
- id: PMID:19946888
  title: Defining the membrane proteome of NK cells.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: NK-cell membrane proteome MS dataset; source of the generic membrane (GO:0016020) HDA annotation. Abstract-only in cache.
- id: PMID:22119785
  title: Defining human ERAD networks through an integrative mapping strategy.
  findings:
  - statement: Identified EMC8 (as COX4NB) as a high-confidence component of the mammalian ER membrane protein complex (mEMC), establishing EMC complex membership and ER membrane/cytoplasm localization.
    reference_section_type: RESULTS
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Foundational integrative MS study that placed EMC8 (COX4NB) in the mammalian EMC; source of the IDA EMC-complex membership and cytoplasm/ER membrane annotations.
- id: PMID:26496610
  title: A human interactome in three quantitative dimensions organized by stoichiometries and abundances.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: Quantitative interactome; source of an EMC8-EMC2 protein binding IPI. Background interaction data only.
- 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/community analysis; source of an EMC8-EMC2 protein binding IPI.
- id: PMID:29242231
  title: The ER membrane protein complex is a transmembrane domain insertase.
  findings:
  - statement: The EMC is a transmembrane-domain insertase that catalyzes insertion of tail-anchored and other substrates into the ER membrane in a reconstituted system; EMC8 is a subunit of this complex.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Definitive demonstration that EMC is a TMD insertase; basis for the complex-level insertase MF and TA-insertion BP annotations EMC8 contributes to.
- id: PMID:29809151
  title: The ER membrane protein complex interacts cotranslationally to enable biogenesis of multipass membrane proteins.
  findings:
  - statement: EMC engages ribosomes cotranslationally and is required for biogenesis of multipass membrane proteins; depletion of EMC subunits impairs insertion.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Source of IMP membrane insertase activity (contributes_to) and cotranslational multipass insertion BP annotations.
- id: PMID:30021884
  title: Histone Interaction Landscapes Visualized by Crosslinking Mass Spectrometry in Intact Cell Nuclei.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: Crosslinking-MS study; an unexpected source for an ER-complex subunit, but curated in IntAct as an EMC8-EMC2 protein binding datapoint. Experimental IPI retained as non-core, not removed.
- id: PMID:30415835
  title: EMC Is Required to Initiate Accurate Membrane Protein Topogenesis.
  findings:
  - statement: EMC mediates cotranslational insertion of the first TMD of GPCRs and other multipass proteins and cooperates with Sec61 to ensure accurate topogenesis; EMC knockout impairs correct topology.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Source of IMP membrane insertase activity (contributes_to) and stop-transfer multipass insertion BP annotations.
- 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 EMC8-EMC2 protein binding IPI.
- id: PMID:32439656
  title: Structural basis for membrane insertion by the human ER membrane protein complex.
  findings:
  - statement: Cryo-EM structure of the human nine-subunit EMC; substrate insertion occurs via an enclosed hydrophilic vestibule formed by EMC3 and EMC6, with EMC8 resolved as a cytosolic-facing subunit.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Structure of the human EMC (EMC8 variant); shows the catalytic vestibule is EMC3/EMC6, confirming EMC8 is a non-catalytic subunit. 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 3 interactome; source of an EMC8-EMC2 protein binding IPI.
- id: PMID:35271311
  title: 'OpenCell: Endogenous tagging for the cartography of human cellular organization.'
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: OpenCell endogenous-tagging interactome/localization; source of an EMC8-EMC2 protein binding IPI consistent with EMC membership.
- 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; EMC8 forms a specific cytosolic client-docking interface ("Cyto dock"/"EMC8 site", ~962 A^2 centered on the last helix of EMC8) with CaVbeta3, binding two CaVbeta loops and ordering an otherwise disordered CaVbeta region, demonstrating an EMC8-specific chaperone/assembly role beyond generic insertion.
    reference_section_type: RESULTS
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: PubMed-verified (Nature 2023, PMID:37196677). Provides direct EMC8-specific structural evidence for a client-binding (CaVbeta3) surface, establishing a chaperone/assembly function for EMC8 distinct from the EMC3/EMC6 insertase core.
- id: PMID:32459176
  title: The architecture of EMC reveals a path for membrane protein insertion.
  findings:
  - statement: EMC2 forms an alpha-solenoid that clamps around EMC8 in the cytosolic basket; EMC8 is a ~23 kDa monomer ~44% identical to EMC9, and EMC8 and EMC9 are mutually exclusive subunits (no ternary EMC2-EMC8-EMC9 complex forms), supporting EMC8 as a structural assembly/scaffold subunit of the cytosolic module.
    reference_section_type: RESULTS
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: PubMed-verified (eLife 2020, PMID:32459176). Source of the EMC8-EMC2 clamp interaction and EMC8/EMC9 mutual exclusivity; supports EMC8's cytosolic structural/assembly role.
- id: PMID:35287476
  title: The Function, Structure, and Origins of the ER Membrane Protein Complex.
  findings:
  - statement: Authoritative review of EMC function, structure, and evolution; places EMC2, EMC8, and EMC9 as the cytosolic subunits and EMC8/EMC9 as mutually exclusive paralogs of the cytosolic cradle that engages membrane-protein clients before insertion.
    reference_section_type: LITERATURE_REVIEW
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: PubMed-verified (Annu Rev Biochem 2022, PMID:35287476). Review supporting EMC8's cytosolic placement and EMC8/EMC9 paralog relationship already described in the review.
- id: PMID:38517390
  title: Structural insights into human EMC and its interaction with VDAC.
  findings:
  - statement: Cryo-EM of human EMC apo and VDAC1-bound states at mitochondria-ER contact sites, with a hydrophilic-vestibule "gating plug" conformational change proposed to regulate EMC function; EMC8 is a cytosolic subunit of the complexes studied (no EMC8-specific mechanistic role assigned in this study).
    reference_section_type: RESULTS
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: PubMed-verified (Aging (Albany NY) 2024, PMID:38517390). Structural study of EMC-VDAC1; does not assign an EMC8-specific role but provides context for alternative EMC functional states. Relevance to EMC8 specifically is low.
- id: file:human/EMC8/EMC8-uniprot.txt
  title: UniProt entry O43402 (EMC8_HUMAN), ER membrane protein complex subunit 8
  findings:
  - statement: EMC8 is a cytosolic, peripheral subunit (cytoplasmic side) of the ER membrane protein complex (EMC), an energy-independent TMD insertase for newly synthesized membrane proteins; mediates cotranslational multipass and post-translational tail-anchored insertion. EMC8 and EMC9 are mutually exclusive subunits; EMC8 belongs to the EMC8/EMC9 family and contains an MPN domain.
    reference_section_type: OTHER
core_functions:
- description: Cytosolic, non-catalytic accessory subunit of the ER membrane protein complex (EMC); its core role is to be a constitutive component of the EMC, an ER transmembrane-domain insertase/chaperone, docking onto the EMC2 scaffold on the cytoplasmic side of the ER membrane and providing a cytosolic client-docking surface (e.g., the EMC8 "Cyto dock" for CaVbeta3) during membrane-protein assembly.
  supported_by:
  - reference_id: file:human/EMC8/EMC8-uniprot.txt
    supporting_text: Component of the ER membrane protein complex (EMC)
  - reference_id: PMID:22119785
    supporting_text: we identified 5 additional HCIPs (TTC35, TMEM32/MMGT1, TMEM85, C15orf24 and COX4NB)
  in_complex:
    id: GO:0072546
    label: EMC complex
  locations:
  - id: GO:0005789
    label: endoplasmic reticulum membrane
- description: As part of the EMC, contributes to membrane insertase activity, participating in energy-independent insertion of newly synthesized membrane proteins into the ER membrane (cotranslational multipass insertion via stop-transfer anchors and post-translational tail-anchored protein insertion). EMC8 is not itself catalytic; the insertion vestibule is provided by EMC3/EMC6.
  contributes_to_molecular_function:
    id: GO:0032977
    label: membrane insertase activity
  locations:
  - id: GO:0005789
    label: endoplasmic reticulum membrane
  supported_by:
  - reference_id: file:human/EMC8/EMC8-uniprot.txt
    supporting_text: enables the energy-independent insertion into endoplasmic
  directly_involved_in:
  - id: GO:0071816
    label: tail-anchored membrane protein insertion into ER membrane
  - id: GO:0045050
    label: protein insertion into ER membrane by stop-transfer membrane-anchor sequence
proposed_new_terms: []
suggested_questions:
- question: What is the specific functional role of EMC8 (versus its mutually exclusive paralog EMC9) within the EMC, and do EMC8- and EMC9-containing complexes differ in substrate preference or regulation?
- question: Does the degenerate MPN domain of EMC8 retain any binding or regulatory function, or is it purely structural for incorporation into the complex?
suggested_experiments:
- description: Compare substrate-insertion profiles (e.g., ribosome profiling / proteomics of membrane-protein biogenesis) in EMC8-knockout versus EMC9-knockout versus EMC8/EMC9 double-knockout cells to define paralog-specific contributions to EMC function.
- description: Reconstitute EMC insertase activity in liposomes with and without EMC8 (and with EMC9 substituted) to test whether EMC8 is required for complex assembly, stability, or insertion efficiency of defined substrates.
- description: Use cryo-EM and crosslinking-MS to map the EMC8-EMC2 interface and determine how EMC8 incorporation affects the architecture of the cytosolic cap of the EMC.