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.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0072546 EMC complex | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetic (PAN-GO) assignment of EMC complex membership across the EMC4 family, matching direct experimental and structural evidence. Core structural identity of EMC4. 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. Supporting Evidence: file:human/EMC4/EMC4-uniprot.txt Component of the ER membrane protein complex (EMC). |
| GO:0005789 endoplasmic reticulum membrane | IEA GO_REF:0000044 | ACCEPT | Summary: Electronic transfer of the ER membrane subcellular location from UniProt; the correct and core compartment for the multipass ER membrane subunit EMC4. Reason: Correct core location; redundant with experimental EXP/IDA evidence. Supporting Evidence: file:human/EMC4/EMC4-uniprot.txt SUBCELLULAR LOCATION: Endoplasmic reticulum membrane |
| GO:0005515 protein binding | IPI PMID:31695625 Interaction Between ITM2B and GLUT9 Links Urate Transport to... | KEEP AS NON CORE | 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. 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. Supporting Evidence: file:human/EMC4/EMC4-uniprot.txt Q5J8M3; Q9NRM0-1: SLC2A9 |
| GO:0005515 protein binding | IPI PMID:33845483 Multilevel proteomics reveals host perturbations by SARS-CoV... | KEEP AS NON CORE | 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. 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. Supporting Evidence: file:human/EMC4/EMC4-uniprot.txt Q5J8M3; PRO_0000449624 [P0DTD1]: rep |
| GO:0005515 protein binding | IPI PMID:34232536 Interactomes of SARS-CoV-2 and human coronaviruses reveal ho... | KEEP AS NON CORE | 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. Reason: Real virus-host interactome capture; bare protein binding is uninformative and the viral partner is not part of EMC4's core function. Supporting Evidence: file:human/EMC4/EMC4-uniprot.txt Q5J8M3; PRO_0000449624 [P0DTD1]: rep |
| GO:0005515 protein binding | IPI PMID:36217030 A comprehensive SARS-CoV-2-human protein-protein interactome... | KEEP AS NON CORE | 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. Reason: Real virus-host interactome capture; bare protein binding is uninformative and the viral partner does not reflect EMC4's core insertase scaffolding role. Supporting Evidence: file:human/EMC4/EMC4-uniprot.txt Q5J8M3; PRO_0000449624 [P0DTD1]: rep |
| GO:0005789 endoplasmic reticulum membrane | NAS PMID:29242231 The ER membrane protein complex is a transmembrane domain in... | ACCEPT | Summary: ComplexPortal NAS annotation of ER membrane localization for the EMC, consistent with the experimental evidence and core compartment of EMC4. Reason: Correct core location; consistent with EXP/IDA evidence. Supporting Evidence: file:human/EMC4/EMC4-uniprot.txt SUBCELLULAR LOCATION: Endoplasmic reticulum membrane |
| GO:0045050 protein insertion into ER membrane by stop-transfer membrane-anchor sequence | IDA PMID:29242231 The ER membrane protein complex is a transmembrane domain in... | ACCEPT | Summary: The EMC inserts transmembrane domains, including stop-transfer membrane-anchor sequences of multipass clients; EMC4 is a constitutive subunit. Core complex-level process. Reason: Core EMC-mediated process; the EMC is a demonstrated transmembrane-domain insertase and EMC4 is a structural subunit. Supporting Evidence: PMID:29242231 transmembrane domain insertase |
| GO:0071816 tail-anchored membrane protein insertion into ER membrane | IDA PMID:29242231 The ER membrane protein complex is a transmembrane domain in... | ACCEPT | 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. Reason: Core EMC-mediated process; directly demonstrated for the complex. Supporting Evidence: PMID:29242231 tail-anchored membrane proteins with moderately hydrophobic transmembrane |
| GO:0072546 EMC complex | IPI PMID:32439656 Structural basis for membrane insertion by the human ER memb... | ACCEPT | 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. Reason: Structurally demonstrated core EMC membership. Supporting Evidence: file:human/EMC4/EMC4-uniprot.txt Component of the ER membrane protein complex (EMC). |
| GO:0005789 endoplasmic reticulum membrane | EXP PMID:22119785 Defining human ERAD networks through an integrative mapping ... | ACCEPT | Summary: Experimental ER membrane localization from the foundational ERAD-network mapping study that first identified the EMC (TMEM85). Core compartment. Reason: Experimentally supported core location. Supporting Evidence: file:human/EMC4/EMC4-uniprot.txt SUBCELLULAR LOCATION: Endoplasmic reticulum membrane |
| GO:0032977 membrane insertase activity | IMP PMID:29809151 The ER membrane protein complex interacts cotranslationally ... | ACCEPT | 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). 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. Supporting Evidence: file:human/EMC4/EMC4-uniprot.txt enables the energy-independent insertion into endoplasmic |
| GO:0032977 membrane insertase activity | IMP PMID:30415835 EMC Is Required to Initiate Accurate Membrane Protein Topoge... | ACCEPT | 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. Reason: Complex-level MF correctly qualified contributes_to; EMC4 supports the insertase activity of the EMC. Supporting Evidence: file:human/EMC4/EMC4-uniprot.txt enables the energy-independent insertion into endoplasmic |
| GO:0045050 protein insertion into ER membrane by stop-transfer membrane-anchor sequence | IMP PMID:29809151 The ER membrane protein complex interacts cotranslationally ... | ACCEPT | 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. Reason: Core EMC-mediated process; supported by IMP of EMC subunits. Supporting Evidence: file:human/EMC4/EMC4-uniprot.txt stop-transfer membrane-anchor sequences become ER membrane spanning |
| GO:0005789 endoplasmic reticulum membrane | IDA PMID:32439656 Structural basis for membrane insertion by the human ER memb... | ACCEPT | Summary: Direct (cryo-EM structural) evidence placing EMC4 in the ER membrane as a membrane subunit of the EMC. Core compartment. Reason: Experimentally supported core location. Supporting Evidence: file:human/EMC4/EMC4-uniprot.txt SUBCELLULAR LOCATION: Endoplasmic reticulum membrane |
| GO:0045050 protein insertion into ER membrane by stop-transfer membrane-anchor sequence | IMP PMID:30415835 EMC Is Required to Initiate Accurate Membrane Protein Topoge... | ACCEPT | 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. Reason: Core EMC-mediated process. Supporting Evidence: PMID:30415835 G protein-coupled receptors |
| GO:0016020 membrane | IDA PMID:22119785 Defining human ERAD networks through an integrative mapping ... | KEEP AS NON CORE | Summary: Direct generic membrane localization from the EMC-discovery study; a parent of the specific ER membrane term. Reason: Correct but generic; the ER membrane term captures the informative localization. Supporting Evidence: file:human/EMC4/EMC4-uniprot.txt SUBCELLULAR LOCATION: Endoplasmic reticulum membrane |
| GO:0072546 EMC complex | IDA PMID:22119785 Defining human ERAD networks through an integrative mapping ... | ACCEPT | Summary: Direct experimental identification of EMC4/TMEM85 in the EMC by the foundational ERAD-network mapping study. Core structural identity. Reason: Core EMC membership; directly demonstrated. Supporting Evidence: file:human/EMC4/EMC4-uniprot.txt Component of the ER membrane protein complex (EMC). |
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Download this section (compressed HTML)Q: 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)?
Q: Does the EMC4-GLUT9 interaction represent a productive client-engagement event during GLUT9 biogenesis, and is GLUT9 surface expression EMC4-dependent?
Experiment: 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.
Experiment: 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.
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