id: Q9BV81
gene_symbol: EMC6
product_type: PROTEIN
status: COMPLETE
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: EMC6 (ER membrane protein complex subunit 6; also TMEM93) is a small (110 aa) polytopic ER membrane protein with three transmembrane helices and an N-cytoplasmic/C-lumenal topology. It is a constitutive subunit of the ER membrane protein complex (EMC), a conserved ~9-subunit transmembrane-domain insertase and membrane-protein chaperone of the endoplasmic reticulum. Within the complex, EMC6 packs against the catalytic insertase subunit EMC3 (a member of the YidC/Oxa1/Get1 insertase superfamily) to form the hydrophilic membrane vestibule through which substrate transmembrane domains are inserted. The EMC enables the energy-independent insertion of newly synthesized membrane proteins into the ER membrane, with a preference for transmembrane domains that are weakly hydrophobic or contain destabilizing charged or aromatic residues. It mediates post-translational insertion of tail-anchored proteins and cotranslational insertion and topogenesis of multipass membrane proteins, including setting the N-exo topology of the first transmembrane domain of G protein-coupled receptors. Mutations of EMC6 residues at the cytoplasmic/TM1 boundary (Asp-27, Thr-31) impair client insertion without disrupting complex assembly, demonstrating a direct contribution of EMC6 to the insertase reaction. EMC6 localizes to the ER membrane and is broadly expressed.
existing_annotations:
- term:
    id: GO:0000045
    label: autophagosome assembly
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: Phylogenetic (PAN-GO) propagation of an autophagosome-assembly role across the EMC6 family, derived ultimately from a single 2013 experimental study reporting EMC6 regulation of autophagosome formation. This phenotype is most plausibly an indirect consequence of impaired biogenesis of EMC membrane-protein clients rather than a direct EMC6 function.
    action: KEEP_AS_NON_CORE
    reason: The autophagy role rests on one experimental paper and is likely an indirect downstream effect of the EMC's insertase function; retained but peripheral, not the core EMC6 function.
    supported_by:
    - reference_id: PMID:23182941
      supporting_text: It was shown to regulate
- term:
    id: GO:0072546
    label: EMC complex
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: part_of
  review:
    summary: EMC6 is a constitutive subunit of the ER membrane protein complex; phylogenetic assignment of EMC complex membership is consistent with direct experimental and structural evidence. This is a core structural identity of EMC6.
    action: ACCEPT
    reason: EMC complex membership is the core cellular-component identity of EMC6 and is supported by IDA, cryo-EM structures, and the conserved EMC6 family.
    supported_by:
    - reference_id: file:human/EMC6/EMC6-uniprot.txt
      supporting_text: Component of the ER membrane protein complex (EMC).
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  qualifier: located_in
  review:
    summary: ARBA machine-learning electronic assignment of cytoplasm; EMC6 is an integral ER membrane protein whose site of action is the ER membrane. Cytoplasm is an imprecise parent term relative to the experimentally supported ER membrane localization.
    action: MARK_AS_OVER_ANNOTATED
    reason: Generic and imprecise electronic assignment; the specific and experimentally supported compartment is the ER membrane (GO:0005789).
    supported_by:
    - reference_id: file:human/EMC6/EMC6-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Endoplasmic reticulum membrane'
- term:
    id: GO:0005783
    label: endoplasmic reticulum
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: located_in
  review:
    summary: InterPro-based electronic assignment to the endoplasmic reticulum, consistent with the experimentally supported ER membrane localization but less specific.
    action: KEEP_AS_NON_CORE
    reason: Correct compartment but a parent of the more precise ER membrane term; redundant with experimental ER membrane evidence.
    supported_by:
    - reference_id: file:human/EMC6/EMC6-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Endoplasmic reticulum membrane'
- 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; the correct and core compartment for EMC6.
    action: ACCEPT
    reason: Correct core location; redundant with experimental EXP/IDA evidence.
    supported_by:
    - reference_id: file:human/EMC6/EMC6-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Endoplasmic reticulum membrane'
- term:
    id: GO:0016020
    label: membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: located_in
  review:
    summary: InterPro-based generic membrane assignment, a parent of the specific ER membrane localization.
    action: KEEP_AS_NON_CORE
    reason: Correct but generic; the specific ER membrane term captures the informative localization.
    supported_by:
    - reference_id: file:human/EMC6/EMC6-uniprot.txt
      supporting_text: Multi-pass
- 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.
    action: ACCEPT
    reason: Correct core structural identity; redundant with IDA/IBA evidence.
    supported_by:
    - reference_id: file:human/EMC6/EMC6-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:22119785
  qualifier: enables
  review:
    summary: IntAct interaction (with MMGT1/EMC10) from the foundational human ERAD-network mapping study that first defined the EMC. The interaction is a genuine EMC partnership, but bare protein binding is uninformative and is not elevated to core.
    action: KEEP_AS_NON_CORE
    reason: Real EMC partner interaction but the bare protein binding term is uninformative per curation guidelines.
    supported_by:
    - reference_id: file:human/EMC6/EMC6-uniprot.txt
      supporting_text: 'Q9BV81; Q8N4V1: MMGT1'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:32296183
  qualifier: enables
  review:
    summary: High-throughput binary (HuRI) interactome captures of EMC6 with multiple membrane proteins (AQP6, AQP9, EBP, SLC transporters, etc.), many of which are plausibly EMC clients. Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: High-throughput interactions, partly reflecting client engagement, but the bare term is uninformative and not core.
    supported_by:
    - reference_id: file:human/EMC6/EMC6-uniprot.txt
      supporting_text: 'Q9BV81; O43315: AQP9'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:32439656
  qualifier: enables
  review:
    summary: Interaction evidence from the cryo-EM structural study of the human EMC, reflecting genuine intra-complex EMC partnerships. Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: Real intra-complex interaction but bare protein binding is uninformative; the EMC complex membership term captures the informative content.
    supported_by:
    - reference_id: file:human/EMC6/EMC6-uniprot.txt
      supporting_text: 'Q9BV81; Q8N4V1: MMGT1'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:33961781
  qualifier: enables
  review:
    summary: BioPlex affinity-MS interactome capture (with MMGT1/EMC10). Genuine EMC partner but the bare term 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/EMC6/EMC6-uniprot.txt
      supporting_text: 'Q9BV81; Q8N4V1: MMGT1'
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: NAS
  original_reference_id: PMID:29242231
  qualifier: located_in
  review:
    summary: ComplexPortal NAS annotation of ER membrane localization for the EMC, consistent with experimental evidence and the core compartment of EMC6.
    action: ACCEPT
    reason: Correct core location; consistent with EXP/IDA evidence.
    supported_by:
    - reference_id: file:human/EMC6/EMC6-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 of multipass proteins; EMC6 is integral to the insertase vestibule. A core biological process of the EMC.
    action: ACCEPT
    reason: Core EMC-mediated process; EMC6 contributes directly via the EMC3/EMC6 insertase vestibule.
    supported_by:
    - reference_id: PMID:29242231
      supporting_text: EMC is a transmembrane domain insertase
- 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 with moderately hydrophobic TMDs; demonstrated directly in this study. A core EMC process to which EMC6 contributes.
    action: ACCEPT
    reason: Core EMC-mediated process; directly demonstrated.
    supported_by:
    - reference_id: PMID:29242231
      supporting_text: tail-anchored membrane proteins with moderately hydrophobic transmembrane
- term:
    id: GO:0072546
    label: EMC complex
  evidence_type: IPI
  original_reference_id: PMID:32439656
  qualifier: part_of
  review:
    summary: ComplexPortal IPI assignment of EMC complex membership based on the cryo-EM structure of the human EMC. Core structural identity of EMC6.
    action: ACCEPT
    reason: Structurally demonstrated core EMC membership.
    supported_by:
    - reference_id: file:human/EMC6/EMC6-uniprot.txt
      supporting_text: Component of the ER membrane protein complex (EMC).
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: EXP
  original_reference_id: PMID:22119785
  qualifier: located_in
  review:
    summary: Experimental ER membrane localization from the EMC-discovery ERAD-network study. Core compartment.
    action: ACCEPT
    reason: Experimentally supported core location.
    supported_by:
    - reference_id: file:human/EMC6/EMC6-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Endoplasmic reticulum membrane'
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: EXP
  original_reference_id: PMID:30415835
  qualifier: located_in
  review:
    summary: Experimental ER membrane localization from the EMC topogenesis study. Core compartment.
    action: ACCEPT
    reason: Experimentally supported core location.
    supported_by:
    - reference_id: file:human/EMC6/EMC6-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Endoplasmic reticulum membrane'
- term:
    id: GO:0032977
    label: membrane insertase activity
  evidence_type: IMP
  original_reference_id: PMID:34918864
  qualifier: contributes_to
  review:
    summary: In vivo Drosophila evidence that the EMC (including EMC6) is required for TMD membrane insertion of a tail-anchored client; combined with the human mutagenesis showing EMC6 D27/T31 reduce insertion without affecting assembly, EMC6 directly contributes to the insertase reaction. The contributes_to qualifier is appropriate for a catalytic-core subunit.
    action: ACCEPT
    reason: EMC6 partners EMC3 in the catalytic insertase vestibule; mutagenesis separates its insertion role from assembly, making membrane insertase activity a defensible core MF (contributes_to).
    supported_by:
    - reference_id: file:human/EMC6/EMC6-uniprot.txt
      supporting_text: No effect on EMC assembly but decreased
- term:
    id: GO:0071816
    label: tail-anchored membrane protein insertion into ER membrane
  evidence_type: IMP
  original_reference_id: PMID:34918864
  qualifier: involved_in
  review:
    summary: In vivo (Drosophila) IMP evidence that the EMC, including EMC6, is required for tail-anchored membrane protein insertion. Core EMC process.
    action: ACCEPT
    reason: Core EMC process; supported by in vivo loss-of-function.
    supported_by:
    - reference_id: PMID:29242231
      supporting_text: tail-anchored membrane proteins with moderately hydrophobic transmembrane
- 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; EMC6 contributes to the insertase activity of the complex. Defensible core MF for a catalytic-core subunit.
    action: ACCEPT
    reason: EMC6 forms the catalytic insertase vestibule with EMC3; contributes_to membrane insertase activity is core.
    supported_by:
    - reference_id: file:human/EMC6/EMC6-uniprot.txt
      supporting_text: No effect on EMC assembly but decreased
- 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 EMC6 contributes as part of the EMC3/EMC6 vestibule. Defensible core MF.
    action: ACCEPT
    reason: Core MF; EMC6 contributes to the insertase reaction.
    supported_by:
    - reference_id: file:human/EMC6/EMC6-uniprot.txt
      supporting_text: No effect on EMC assembly but decreased
- 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; EMC6 is part of the insertase. Core EMC process.
    action: ACCEPT
    reason: Core EMC-mediated process; supported by IMP of EMC subunits.
    supported_by:
    - reference_id: file:human/EMC6/EMC6-uniprot.txt
      supporting_text: stop-transfer membrane-anchor sequences become ER membrane spanning
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: IDA
  original_reference_id: PMID:32439656
  qualifier: located_in
  review:
    summary: Direct (structural) evidence placing EMC6 in the ER membrane. Core compartment.
    action: ACCEPT
    reason: Experimentally supported core location.
    supported_by:
    - reference_id: file:human/EMC6/EMC6-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: 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 and N-exo topogenesis of multipass clients. Core EMC process.
    action: ACCEPT
    reason: Core EMC-mediated process.
    supported_by:
    - reference_id: PMID:30415835
      supporting_text: G protein-coupled receptors (GPCRs)
- term:
    id: GO:0071816
    label: tail-anchored membrane protein insertion into ER membrane
  evidence_type: IMP
  original_reference_id: PMID:29242231
  qualifier: involved_in
  review:
    summary: IMP evidence that the EMC is required for tail-anchored protein insertion into the ER membrane; EMC6 is part of the insertase. Core EMC process.
    action: ACCEPT
    reason: Core EMC-mediated process; directly demonstrated.
    supported_by:
    - reference_id: PMID:29242231
      supporting_text: tail-anchored membrane proteins with moderately hydrophobic transmembrane
- term:
    id: GO:0000045
    label: autophagosome assembly
  evidence_type: IMP
  original_reference_id: PMID:23182941
  qualifier: involved_in
  review:
    summary: A single 2013 study reported that EMC6 interacts with RAB5A and BECN1, colocalizes with the omegasome marker ZFYVE1/DFCP1, and that its deficiency impairs autophagosome formation. The curator read the full text, so the experimental annotation is retained, but this autophagy role is most plausibly an indirect consequence of impaired EMC client biogenesis and is not the core EMC6 function.
    action: KEEP_AS_NON_CORE
    reason: Genuine experimental observation but likely indirect (secondary to the EMC insertase role); not core. Per guidelines an experimental IMP is not removed on incomplete cached evidence.
    supported_by:
    - reference_id: PMID:23182941
      supporting_text: It was shown to regulate
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:23182941
  qualifier: enables
  review:
    summary: IPI interactions (with RAB5A and BECN1) from the autophagy study. Bare protein binding is uninformative and these partners are peripheral to the core EMC insertase function.
    action: KEEP_AS_NON_CORE
    reason: Real but peripheral interactions; bare protein binding is uninformative per guidelines.
    supported_by:
    - reference_id: PMID:23182941
      supporting_text: interacts with RAB5A
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: IDA
  original_reference_id: PMID:23182941
  qualifier: located_in
  review:
    summary: Direct evidence that EMC6 is an ER-localized transmembrane protein. Core compartment.
    action: ACCEPT
    reason: Experimentally supported core location.
    supported_by:
    - reference_id: PMID:23182941
      supporting_text: ER-localized transmembrane protein
- term:
    id: GO:1903349
    label: omegasome membrane
  evidence_type: IDA
  original_reference_id: PMID:23182941
  qualifier: located_in
  review:
    summary: EMC6 was reported to colocalize with the omegasome marker ZFYVE1/DFCP1 in the 2013 autophagy study. This is a specialized localization tied to the autophagy phenotype, peripheral to EMC6's core ER-membrane insertase role and likely reflecting partial overlap with ER-derived omegasome subdomains.
    action: KEEP_AS_NON_CORE
    reason: Experimentally reported but peripheral, tied to the (likely indirect) autophagy role; not the core localization.
    supported_by:
    - reference_id: PMID:23182941
      supporting_text: colocalized with the omegasome marker ZFYVE1/DFCP1
- term:
    id: GO:0016020
    label: membrane
  evidence_type: IDA
  original_reference_id: PMID:22119785
  qualifier: located_in
  review:
    summary: Direct generic membrane localization from the EMC-discovery study; a parent of the specific ER membrane term.
    action: KEEP_AS_NON_CORE
    reason: Correct but generic; the ER membrane term captures the informative localization.
    supported_by:
    - reference_id: file:human/EMC6/EMC6-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Endoplasmic reticulum membrane'
- term:
    id: GO:0072546
    label: EMC complex
  evidence_type: IDA
  original_reference_id: PMID:22119785
  qualifier: part_of
  review:
    summary: Direct experimental identification of EMC6 in the EMC by the foundational ERAD-network mapping study. Core structural identity.
    action: ACCEPT
    reason: Core EMC membership; directly demonstrated.
    supported_by:
    - reference_id: file:human/EMC6/EMC6-uniprot.txt
      supporting_text: Component of the ER membrane protein complex (EMC).
core_functions:
- description: Constitutive subunit of the ER membrane protein complex (EMC) that, together with EMC3, forms the membrane-embedded hydrophilic insertase vestibule, contributing to the energy-independent insertion of transmembrane domains into the ER membrane.
  molecular_function:
    id: GO:0032977
    label: membrane insertase activity
  in_complex:
    id: GO:0072546
    label: EMC complex
  locations:
  - id: GO:0005789
    label: endoplasmic reticulum membrane
  supported_by:
  - reference_id: file:human/EMC6/EMC6-uniprot.txt
    supporting_text: No effect on EMC assembly but decreased
  - reference_id: PMID:29242231
    supporting_text: EMC is a transmembrane domain insertase
  - reference_id: PMID:37199759
    supporting_text: The EMC3/EMC6 hydrophilic vestibule is the central insertion route and bears a charge-based selectivity filter that enforces correct topology.
    full_text_unavailable: true
  - reference_id: PMID:38517390
    supporting_text: EMC6 is part of the EMC3-EMC6 core forming the hydrophilic vestibule, with a gating plug that regulates the vestibule between functional states.
    full_text_unavailable: true
- description: As part of the EMC, contributes to post-translational insertion of tail-anchored proteins and cotranslational insertion and N-exo topogenesis of multipass membrane proteins (including GPCRs) at the ER membrane.
  molecular_function:
    id: GO:0032977
    label: membrane insertase activity
  locations:
  - id: GO:0005789
    label: endoplasmic reticulum membrane
  supported_by:
  - reference_id: file:human/EMC6/EMC6-uniprot.txt
    supporting_text: required for the
  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: []
references:
- id: PMID:32459176
  title: The architecture of EMC reveals a path for membrane protein insertion.
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: 'O''Donnell et al. 2020 (eLife). Cryo-EM architecture of the human EMC,
      establishing the overall complex organization and subunit topology relevant to
      EMC6 as a constitutive EMC subunit.'
- 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:0000117
  title: Electronic Gene Ontology annotations created by ARBA machine learning models
  findings: []
- 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 EMC6) in human cells and localized it to the ER membrane.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Foundational identification of the human EMC; source of EMC complex membership and ER membrane localization for EMC6.
- id: PMID:23182941
  title: A novel ER-localized transmembrane protein, EMC6, interacts with RAB5A and regulates cell autophagy.
  findings:
  - statement: EMC6 interacts with RAB5A and BECN1, colocalizes with the omegasome marker ZFYVE1/DFCP1, and its deficiency impairs autophagosome formation.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: Single experimental study predating the insertase understanding of EMC; the autophagy/omegasome phenotype is plausibly an indirect downstream effect of impaired EMC client biogenesis. Abstract-only in cache.
- id: PMID:29242231
  title: The ER membrane protein complex is a transmembrane domain insertase.
  findings:
  - statement: EMC is a transmembrane domain insertase that post-translationally inserts tail-anchored membrane proteins with moderately hydrophobic TMDs.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Establishes the insertase function of the EMC; basis for the insertion BP/MF annotations.
- 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 GPCRs and other multipass proteins, initiating accurate topogenesis.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Topogenesis/orientation role of the EMC; GPCR clients.
- id: PMID:32296183
  title: A reference map of the human binary protein interactome.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: High-throughput HuRI binary interactome; source of several IPI protein-binding partners (membrane-protein clients).
- 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; substrate insertion occurs via an enclosed hydrophilic vestibule formed by EMC3 and EMC6, and EMC6 D27/T31 mutants reduce insertion without disrupting assembly.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Structural basis for the EMC3/EMC6 insertase vestibule; mutagenesis separating EMC6's insertion role from assembly. 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 (MMGT1/EMC10).
- id: PMID:34918864
  title: EMC is required for biogenesis of Xport-A, an essential chaperone of Rhodopsin-1 and the TRP channel.
  findings:
  - statement: In vivo Drosophila evidence that the EMC, including EMC6, is required for TMD membrane insertion of the tail-anchored client Xport-A.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: In vivo loss-of-function support for the EMC insertase function; basis for the FlyBase IMP annotations.
- id: PMID:37199759
  title: A selectivity filter in the ER membrane protein complex limits protein misinsertion at the ER.
  findings:
  - statement: An improved human EMC model defines a charge-based selectivity filter at the hydrophilic vestibule that rejects mitochondrial tail-anchored proteins and enforces the positive-inside rule; the EMC3/EMC6 vestibule remains the central insertion route.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: PubMed-verified (J Cell Biol 2023). Recent mechanistic refinement consolidating the EMC3/EMC6 vestibule as the insertion/selectivity route; supports EMC6's core insertase-vestibule role (EMC6 mutations had milder effects than EMC3 in the tested context).
- id: PMID:37196677
  title: 'EMC chaperone-Ca(V) structure reveals an ion channel assembly intermediate.'
  findings:
  - statement: Cryo-EM of an EMC-bound CaV1.2 assembly intermediate shows the EMC acts as a holdase/chaperone during multipass channel assembly, defining TM and Cyto client-docking sites, supporting that EMC function extends beyond insertion to assembly of complex multipass clients.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: PubMed-verified (Nature 2023). Establishes a holdase/chaperone mode of the EMC for a multipass client; supports the multipass biogenesis processes to which the EMC3/EMC6 core contributes.
- id: PMID:38517390
  title: Structural insights into human EMC and its interaction with VDAC.
  findings:
  - statement: Cryo-EM structures of human EMC in apo and VDAC-bound states place EMC6 in the EMC3-EMC6 core; a gating plug (assigned to EMC3) within the hydrophilic vestibule changes conformation between states, and the EMC engages VDAC at mitochondria-ER contact sites.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: PubMed-verified (Aging 2024). Independent human EMC structure confirming EMC6 as part of the EMC3-EMC6 vestibule core; documents state-dependent vestibule regulation and an EMC-VDAC interaction at MERCs.
- id: PMID:40753078
  title: The EMC acts as a chaperone for membrane proteins.
  findings:
  - statement: The EMC has a chaperone function in addition to insertase activity; EMC6 is named as part of a lipid-filled cavity formed by EMC1/EMC3/EMC5/EMC6 distinct from the canonical insertase site, supporting a broader EMC quality-control/chaperone role.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: PubMed-verified (Nat Commun 2025). Defines an additional EMC chaperone mode and places EMC6 in a distinct lipid-filled cavity; supports the broader membrane-protein biogenesis role of the EMC core including EMC6.
- id: file:human/EMC6/EMC6-uniprot.txt
  title: UniProt entry Q9BV81 (EMC6_HUMAN), ER membrane protein complex subunit 6
  findings:
  - statement: Three-TM ER membrane subunit of the EMC; with EMC3 forms the insertase vestibule; EMC6 D27/T31 mutants reduce client insertion without affecting assembly.
    reference_section_type: OTHER
suggested_questions:
- question: Is the autophagosome-assembly phenotype of EMC6 loss a direct function or an indirect consequence of failed biogenesis of specific autophagy-related membrane-protein clients?
- question: What is the precise contribution of EMC6's TM1 residues (Asp-27, Thr-31) to the energetics of substrate TMD insertion through the EMC3/EMC6 vestibule?
suggested_experiments:
- description: Define the endogenous EMC6-dependent client repertoire by quantitative membrane proteomics in EMC6-knockout versus rescued cells, distinguishing direct insertase substrates from indirectly affected proteins (including autophagy machinery).
- description: Reconstitute insertion of model tail-anchored and multipass substrates into proteoliposomes with wild-type versus D27A/T31A EMC6 to quantify the residue-specific contribution of EMC6 to insertion efficiency independent of complex assembly.