id: Q5J8M3
gene_symbol: EMC4
product_type: PROTEIN
status: COMPLETE
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: EMC4 (ER membrane protein complex subunit 4; also TMEM85) is a small (~183-residue, ~20 kDa) polytopic ER membrane protein and a constitutive structural subunit of the ER membrane protein complex (EMC), a conserved nine- to ten-subunit transmembrane-domain insertase and membrane-protein chaperone of the endoplasmic reticulum. Cryo-EM structures resolve EMC4 with a cytoplasmic N-terminus, transmembrane segments, and a lumenal C-terminus, packing against the other membrane subunits to help form and stabilize the complex. EMC4 is not part of the catalytic insertase core, which is formed by the EMC3 and EMC6 subunits that build the membrane-embedded hydrophilic substrate vestibule; instead EMC4 is an accessory/scaffold subunit. As part of the EMC it contributes to the 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 or aromatic residues. The complex mediates post-translational insertion of tail-anchored proteins and cotranslational insertion and N-exo topogenesis of multipass membrane proteins, including transporters and G protein-coupled receptors, in cooperation with the Sec61 translocon. EMC4 is broadly expressed and resides in the ER membrane.
alternative_products:
- name: 1 (TMEM85v1)
  id: Q5J8M3-1
- name: 2 (TMEM85v2)
  id: Q5J8M3-2
  sequence_note: VSP_020798, VSP_020799
- name: '3'
  id: Q5J8M3-3
  sequence_note: VSP_037374, VSP_037375
existing_annotations:
- term:
    id: GO:0072546
    label: EMC complex
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: part_of
  review:
    summary: Phylogenetic (PAN-GO) assignment of EMC complex membership across the EMC4 family, matching direct experimental and structural evidence. Core structural identity of EMC4.
    action: ACCEPT
    reason: EMC complex membership is the core cellular-component identity of EMC4 and is supported by IDA, cryo-EM structures, and the conserved EMC4 family.
    supported_by:
    - reference_id: file:human/EMC4/EMC4-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; the correct and core compartment for the multipass ER membrane subunit EMC4.
    action: ACCEPT
    reason: Correct core location; redundant with experimental EXP/IDA evidence.
    supported_by:
    - reference_id: file:human/EMC4/EMC4-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Endoplasmic reticulum membrane'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:31695625
  qualifier: enables
  review:
    summary: IntAct interaction of EMC4/TMEM85 with the multipass urate transporter GLUT9/SLC2A9 (Q9NRM0). In the functional assay TMEM85 (unlike ITM2B) did not affect GLUT9-mediated urate uptake; the interaction most plausibly reflects EMC4 engaging GLUT9 as an EMC client (consistent with the EMC's transporter-client preference). Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: Plausible EMC-client (transporter) interaction, but bare protein binding is uninformative per curation guidelines and the functional assay showed no role of TMEM85 in urate transport itself; not elevated to core.
    supported_by:
    - reference_id: file:human/EMC4/EMC4-uniprot.txt
      supporting_text: 'Q5J8M3; Q9NRM0-1: SLC2A9'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:33845483
  qualifier: enables
  review:
    summary: High-throughput SARS-CoV-2/SARS-CoV proteomics interactome capturing EMC4 with the viral replicase polyprotein (P0DTD1, rep). Bare protein binding is uninformative and the partner is a viral xenobiotic protein unrelated to EMC4's core function.
    action: KEEP_AS_NON_CORE
    reason: Real virus-host interactome capture but bare protein binding is uninformative; the viral partner does not inform EMC4's core ER insertase scaffolding role.
    supported_by:
    - reference_id: file:human/EMC4/EMC4-uniprot.txt
      supporting_text: 'Q5J8M3; PRO_0000449624 [P0DTD1]: rep'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:34232536
  qualifier: enables
  review:
    summary: Comparative coronavirus interactome screen capturing the EMC4-viral replicase (P0DTD1, rep) interaction. Bare protein binding is uninformative and the partner is a viral protein.
    action: KEEP_AS_NON_CORE
    reason: Real virus-host interactome capture; bare protein binding is uninformative and the viral partner is not part of EMC4's core function.
    supported_by:
    - reference_id: file:human/EMC4/EMC4-uniprot.txt
      supporting_text: 'Q5J8M3; PRO_0000449624 [P0DTD1]: rep'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:36217030
  qualifier: enables
  review:
    summary: Comprehensive SARS-CoV-2-human interactome capturing the EMC4-viral replicase (P0DTD1, rep) interaction. Bare protein binding is uninformative and the partner is a viral protein.
    action: KEEP_AS_NON_CORE
    reason: Real virus-host interactome capture; bare protein binding is uninformative and the viral partner does not reflect EMC4's core insertase scaffolding role.
    supported_by:
    - reference_id: file:human/EMC4/EMC4-uniprot.txt
      supporting_text: 'Q5J8M3; PRO_0000449624 [P0DTD1]: rep'
- 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 the experimental evidence and core compartment of EMC4.
    action: ACCEPT
    reason: Correct core location; consistent with EXP/IDA evidence.
    supported_by:
    - reference_id: file:human/EMC4/EMC4-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 clients; EMC4 is a constitutive subunit. Core complex-level process.
    action: ACCEPT
    reason: Core EMC-mediated process; the EMC is a demonstrated transmembrane-domain insertase and EMC4 is a structural subunit.
    supported_by:
    - reference_id: PMID:29242231
      supporting_text: 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; EMC4 is a constitutive subunit. Core complex-level process.
    action: ACCEPT
    reason: Core EMC-mediated process; directly demonstrated for the complex.
    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, which resolves EMC4 as a membrane subunit. Core structural identity.
    action: ACCEPT
    reason: Structurally demonstrated core EMC membership.
    supported_by:
    - reference_id: file:human/EMC4/EMC4-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 foundational ERAD-network mapping study that first identified the EMC (TMEM85). Core compartment.
    action: ACCEPT
    reason: Experimentally supported core location.
    supported_by:
    - reference_id: file:human/EMC4/EMC4-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Endoplasmic reticulum membrane'
- term:
    id: GO:0032977
    label: membrane insertase activity
  evidence_type: IMP
  original_reference_id: PMID:29809151
  qualifier: contributes_to
  review:
    summary: IMP evidence (cotranslational multipass biogenesis study) that the EMC has membrane insertase activity, to which EMC4 contributes as a structural subunit. The contributes_to qualifier is appropriate because EMC4 is not catalytic (the vestibule is EMC3/EMC6).
    action: ACCEPT
    reason: Complex-level MF correctly qualified contributes_to; EMC4 supports the insertase activity of the EMC as an accessory membrane subunit but is not itself catalytic.
    supported_by:
    - reference_id: file:human/EMC4/EMC4-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 (topogenesis study) supporting the EMC's membrane insertase activity, to which EMC4 contributes as a structural subunit. contributes_to correctly reflects that EMC4 is non-catalytic.
    action: ACCEPT
    reason: Complex-level MF correctly qualified contributes_to; EMC4 supports the insertase activity of the EMC.
    supported_by:
    - reference_id: file:human/EMC4/EMC4-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: 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; EMC4 is a constitutive subunit. Core EMC process.
    action: ACCEPT
    reason: Core EMC-mediated process; supported by IMP of EMC subunits.
    supported_by:
    - reference_id: file:human/EMC4/EMC4-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 (cryo-EM structural) evidence placing EMC4 in the ER membrane as a membrane subunit of the EMC. Core compartment.
    action: ACCEPT
    reason: Experimentally supported core location.
    supported_by:
    - reference_id: file:human/EMC4/EMC4-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 evidence (topogenesis study) that the EMC inserts stop-transfer membrane-anchor sequences and sets the N-exo topology of multipass clients such as GPCRs; EMC4 is part of the insertase complex. Core EMC process.
    action: ACCEPT
    reason: Core EMC-mediated process.
    supported_by:
    - reference_id: PMID:30415835
      supporting_text: G protein-coupled receptors
- 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/EMC4/EMC4-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 EMC4/TMEM85 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/EMC4/EMC4-uniprot.txt
      supporting_text: Component of the ER membrane protein complex (EMC).
core_functions:
- description: Constitutive accessory/structural membrane subunit of the ER membrane protein complex (EMC); packs against the other membrane subunits to help form and stabilize the complex and contributes to its energy-independent membrane insertase activity, while the catalytic vestibule is formed by EMC3 and EMC6.
  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/EMC4/EMC4-uniprot.txt
    supporting_text: Component of the ER membrane protein complex (EMC).
  - reference_id: file:human/EMC4/EMC4-uniprot.txt
    supporting_text: enables the energy-independent insertion into endoplasmic
  - reference_id: PMID:37199759
    supporting_text: EMC4 is resolved as a three-TMD subunit that, with EMC7/EMC10, partially encloses the hydrophilic insertase vestibule and contacts substrates at the client-facing surface.
    full_text_unavailable: true
  - reference_id: PMID:38517390
    supporting_text: EMC4 forms an ordered three-TMH bundle adjacent to the EMC3/EMC6 core, constituting a sidewall of the hydrophilic vestibule.
    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 transporters and 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/EMC4/EMC4-uniprot.txt
    supporting_text: post-translational insertion of tail-anchored/TA proteins in
  - reference_id: PMID:37196677
    supporting_text: EMC4 participates in the client-engaging cytoplasmic chaperone module and lumenal EMC1/EMC4/EMC7/EMC10 subassembly during assembly of the multipass CaV1.2 channel.
    full_text_unavailable: true
  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
      EMC4 as a constitutive EMC subunit.'
- 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:22119785
  title: Defining human ERAD networks through an integrative mapping strategy.
  findings:
  - statement: Affinity-MS ERAD-network mapping that first identified the EMC (including TMEM85/EMC4) 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 EMC4.
- 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, with a particular enrichment for transporters, to enable their biogenesis.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Cotranslational multipass biogenesis role of the EMC (transporter clients); basis for the IMP MF/BP annotations.
- 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 in cooperation with Sec61.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Topogenesis/orientation role of the EMC; GPCR clients; basis for IMP MF/BP annotations.
- id: PMID:31695625
  title: Interaction Between ITM2B and GLUT9 Links Urate Transport to Neurodegenerative Disorders.
  findings:
  - statement: TMEM85/EMC4 interacts with GLUT9/SLC2A9, but ITM2B (not TMEM85) inhibited GLUT9-mediated urate uptake.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: Source of the EMC4-GLUT9 IPI; the GLUT9 interaction most plausibly reflects EMC4 engaging a multipass transporter client, but TMEM85 itself did not affect urate transport.
- 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, with EMC4 resolved as a membrane subunit of the complex.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Structural basis for the EMC; confirms EMC4 as a (non-catalytic) membrane subunit. Abstract-only in cache.
- id: PMID:33845483
  title: Multilevel proteomics reveals host perturbations by SARS-CoV-2 and SARS-CoV.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: High-throughput virus-host proteomics; source of an IPI protein-binding annotation with the viral replicase (P0DTD1).
- id: PMID:34232536
  title: Interactomes of SARS-CoV-2 and human coronaviruses reveal host factors potentially affecting pathogenesis.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: Comparative coronavirus interactome; source of an IPI protein-binding annotation with the viral replicase (P0DTD1).
- id: PMID:36217030
  title: A comprehensive SARS-CoV-2-human protein-protein interactome reveals COVID-19 pathobiology and potential host therapeutic targets.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: Comprehensive SARS-CoV-2-human interactome; source of an IPI protein-binding annotation with the viral replicase (P0DTD1).
- id: PMID:37199759
  title: A selectivity filter in the ER membrane protein complex limits protein misinsertion at the ER.
  findings:
  - statement: Improved cryo-EM model of human EMC assigns three transmembrane domains to EMC4; EMC4/EMC7/EMC10 TMDs partially enclose the hydrophilic insertase vestibule, and substrate photocrosslinking/disulfide crosslinking detects contacts with EMC4 as well as EMC3.
    reference_section_type: RESULTS
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: PubMed-verified (J Cell Biol 2023). Recent structural/mechanistic study that resolves EMC4 as a three-TMD vestibule-enclosing subunit and places it at the client-facing surface; directly supports EMC4's structural role in the insertase and the membrane insertase activity annotation.
- 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 voltage-gated calcium channel assembly; EMC4 participates in the client-engaging cytoplasmic chaperone module and in a lumenal EMC1/EMC4/EMC7/EMC10 subassembly.
    reference_section_type: RESULTS
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: PubMed-verified (Nature 2023). Establishes a holdase/chaperone mode of the EMC for a multipass client and places EMC4 directly in the client-handling architecture; supports EMC4's role in multipass membrane protein biogenesis.
- 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; EMC4 forms an ordered three-TMH bundle adjacent to the EMC3/EMC6 core that constitutes a sidewall of the hydrophilic vestibule, and the EMC engages VDAC at mitochondria-ER contact sites.
    reference_section_type: RESULTS
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: PubMed-verified (Aging 2024). Independent human EMC structure corroborating EMC4 as a three-TMH vestibule sidewall subunit; supports EMC4's ER-membrane structural role.
- id: PMID:38621120
  title: Lipid scrambling is a general feature of protein insertases.
  findings:
  - statement: Reconstitution and coarse-grained MD indicate lipid scrambling is a general feature of protein insertases, with EMC scrambling activity localized to EMC3 and EMC4; scrambling occurs in the same hydrophilic channel used for protein insertion.
    reference_section_type: RESULTS
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: PubMed-verified (PNAS 2024). Computational/biochemical proposal of an additional lipid-scramblase activity attributed to EMC3/EMC4; hypothesis-generating for a possible EMC4 function beyond protein insertion (not yet demonstrated for human EMC4 in cells).
- id: PMID:31273220
  title: 'Dual roles for the ER membrane protein complex in flavivirus infection: viral entry and protein biogenesis.'
  findings:
  - statement: EMC4 is a proviral host factor for dengue, yellow fever, and Zika viruses, acting both at an early entry/uncoating step and in biogenesis of viral multipass membrane proteins; EMC4 knockout/knockdown strongly reduces infectivity and viral titers.
    reference_section_type: RESULTS
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: PubMed-verified (Sci Rep 2019). EMC4-specific functional genetics establishing it as a flavivirus host dependency factor, consistent with the EMC's role in viral multipass membrane-protein biogenesis.
- id: PMID:31067454
  title: The ER Membrane Protein Complex Promotes Biogenesis of Dengue and Zika Virus Non-structural Multi-pass Transmembrane Proteins to Support Infection.
  findings:
  - statement: The EMC promotes biogenesis of flavivirus non-structural multipass transmembrane proteins (e.g., NS4B); EMC associates with these viral clients, consistent with a direct role in viral membrane-protein biogenesis.
    reference_section_type: RESULTS
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: PubMed-verified (Cell Reports 2019). Mechanistic support that the EMC (engaging clients such as NS4B) supports flavivirus multipass protein biogenesis; corroborates EMC4's antiviral host-factor role.
- id: PMID:32111841
  title: Selective EMC subunits act as molecular tethers of intracellular organelles exploited during viral entry.
  findings:
  - statement: EMC4 and EMC7 promote late endosome-to-ER targeting of polyomavirus SV40 during entry; EMC4 engages Rab7 and syntaxin18 and is proposed to act as a tether stabilizing late endosome-ER contacts, with EMC4-FLAG rescue supporting specificity.
    reference_section_type: RESULTS
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: PubMed-verified (Nat Commun 2020). EMC4-specific role in organelle tethering/viral trafficking, partly distinct from the bulk EMC insertase function; informative non-core context.
- id: file:human/EMC4/EMC4-uniprot.txt
  title: UniProt entry Q5J8M3 (EMC4_HUMAN), ER membrane protein complex subunit 4
  findings:
  - statement: Small polytopic ER membrane accessory subunit of the EMC (TMEM85); structural/scaffold subunit, not part of the EMC3/EMC6 catalytic vestibule; interacts with the EMC client transporter GLUT9/SLC2A9.
    reference_section_type: OTHER
suggested_questions:
- question: What specific structural role does EMC4 play in EMC assembly and stability, and does loss of EMC4 selectively impair insertion of particular client classes (e.g. multipass transporters)?
- question: Does the EMC4-GLUT9 interaction represent a productive client-engagement event during GLUT9 biogenesis, and is GLUT9 surface expression EMC4-dependent?
suggested_experiments:
- description: Knock out EMC4 in human cells and perform quantitative membrane proteomics with rescue to define the EMC4-dependent client repertoire and distinguish it from clients tolerant of EMC4 loss.
- description: Test EMC4 dependence of GLUT9 and other candidate transporter clients by measuring their folding, ER export and plasma-membrane levels in EMC4-depleted versus rescued cells.