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.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0000045 autophagosome assembly | IBA GO_REF:0000033 | KEEP AS NON CORE | 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. 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. Supporting Evidence: PMID:23182941 It was shown to regulate |
| GO:0072546 EMC complex | IBA GO_REF:0000033 | ACCEPT | 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. 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. Supporting Evidence: file:human/EMC6/EMC6-uniprot.txt Component of the ER membrane protein complex (EMC). |
| GO:0005737 cytoplasm | IEA GO_REF:0000117 | MARK AS OVER ANNOTATED | 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. Reason: Generic and imprecise electronic assignment; the specific and experimentally supported compartment is the ER membrane (GO:0005789). Supporting Evidence: file:human/EMC6/EMC6-uniprot.txt SUBCELLULAR LOCATION: Endoplasmic reticulum membrane |
| GO:0005783 endoplasmic reticulum | IEA GO_REF:0000002 | KEEP AS NON CORE | Summary: InterPro-based electronic assignment to the endoplasmic reticulum, consistent with the experimentally supported ER membrane localization but less specific. Reason: Correct compartment but a parent of the more precise ER membrane term; redundant with experimental ER membrane evidence. Supporting Evidence: file:human/EMC6/EMC6-uniprot.txt SUBCELLULAR LOCATION: Endoplasmic reticulum membrane |
| 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 EMC6. Reason: Correct core location; redundant with experimental EXP/IDA evidence. Supporting Evidence: file:human/EMC6/EMC6-uniprot.txt SUBCELLULAR LOCATION: Endoplasmic reticulum membrane |
| GO:0016020 membrane | IEA GO_REF:0000002 | KEEP AS NON CORE | Summary: InterPro-based generic membrane assignment, a parent of the specific ER membrane localization. Reason: Correct but generic; the specific ER membrane term captures the informative localization. Supporting Evidence: file:human/EMC6/EMC6-uniprot.txt Multi-pass |
| GO:0072546 EMC complex | IEA GO_REF:0000002 | ACCEPT | Summary: InterPro-based electronic assignment of EMC complex membership, consistent with the experimental IDA annotation. Reason: Correct core structural identity; redundant with IDA/IBA evidence. Supporting Evidence: file:human/EMC6/EMC6-uniprot.txt Component of the ER membrane protein complex (EMC). |
| GO:0005515 protein binding | IPI PMID:22119785 Defining human ERAD networks through an integrative mapping ... | KEEP AS NON CORE | 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. Reason: Real EMC partner interaction but the bare protein binding term is uninformative per curation guidelines. Supporting Evidence: file:human/EMC6/EMC6-uniprot.txt Q9BV81; Q8N4V1: MMGT1 |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | KEEP AS NON CORE | 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. Reason: High-throughput interactions, partly reflecting client engagement, but the bare term is uninformative and not core. Supporting Evidence: file:human/EMC6/EMC6-uniprot.txt Q9BV81; O43315: AQP9 |
| GO:0005515 protein binding | IPI PMID:32439656 Structural basis for membrane insertion by the human ER memb... | KEEP AS NON CORE | Summary: Interaction evidence from the cryo-EM structural study of the human EMC, reflecting genuine intra-complex EMC partnerships. Bare protein binding is uninformative. Reason: Real intra-complex interaction but bare protein binding is uninformative; the EMC complex membership term captures the informative content. Supporting Evidence: file:human/EMC6/EMC6-uniprot.txt Q9BV81; Q8N4V1: MMGT1 |
| GO:0005515 protein binding | IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling... | KEEP AS NON CORE | Summary: BioPlex affinity-MS interactome capture (with MMGT1/EMC10). Genuine EMC partner but the bare term is uninformative. Reason: High-throughput interaction; bare protein binding is uninformative and not core. Supporting Evidence: file:human/EMC6/EMC6-uniprot.txt Q9BV81; Q8N4V1: MMGT1 |
| 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 experimental evidence and the core compartment of EMC6. Reason: Correct core location; consistent with EXP/IDA evidence. Supporting Evidence: file:human/EMC6/EMC6-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 proteins; EMC6 is integral to the insertase vestibule. A core biological process of the EMC. Reason: Core EMC-mediated process; EMC6 contributes directly via the EMC3/EMC6 insertase vestibule. Supporting Evidence: PMID:29242231 EMC is a 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. A core EMC process to which EMC6 contributes. Reason: Core EMC-mediated process; directly demonstrated. 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. Core structural identity of EMC6. Reason: Structurally demonstrated core EMC membership. Supporting Evidence: file:human/EMC6/EMC6-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 EMC-discovery ERAD-network study. Core compartment. Reason: Experimentally supported core location. Supporting Evidence: file:human/EMC6/EMC6-uniprot.txt SUBCELLULAR LOCATION: Endoplasmic reticulum membrane |
| GO:0005789 endoplasmic reticulum membrane | EXP PMID:30415835 EMC Is Required to Initiate Accurate Membrane Protein Topoge... | ACCEPT | Summary: Experimental ER membrane localization from the EMC topogenesis study. Core compartment. Reason: Experimentally supported core location. Supporting Evidence: file:human/EMC6/EMC6-uniprot.txt SUBCELLULAR LOCATION: Endoplasmic reticulum membrane |
| GO:0032977 membrane insertase activity | IMP PMID:34918864 EMC is required for biogenesis of Xport-A, an essential chap... | ACCEPT | 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. 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). Supporting Evidence: file:human/EMC6/EMC6-uniprot.txt No effect on EMC assembly but decreased |
| GO:0071816 tail-anchored membrane protein insertion into ER membrane | IMP PMID:34918864 EMC is required for biogenesis of Xport-A, an essential chap... | ACCEPT | Summary: In vivo (Drosophila) IMP evidence that the EMC, including EMC6, is required for tail-anchored membrane protein insertion. Core EMC process. Reason: Core EMC process; supported by in vivo loss-of-function. Supporting Evidence: PMID:29242231 tail-anchored membrane proteins with moderately hydrophobic transmembrane |
| GO:0032977 membrane insertase activity | IMP PMID:29809151 The ER membrane protein complex interacts cotranslationally ... | ACCEPT | 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. Reason: EMC6 forms the catalytic insertase vestibule with EMC3; contributes_to membrane insertase activity is core. Supporting Evidence: file:human/EMC6/EMC6-uniprot.txt No effect on EMC assembly but decreased |
| 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 EMC6 contributes as part of the EMC3/EMC6 vestibule. Defensible core MF. Reason: Core MF; EMC6 contributes to the insertase reaction. Supporting Evidence: file:human/EMC6/EMC6-uniprot.txt No effect on EMC assembly but decreased |
| 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; EMC6 is part of the insertase. Core EMC process. Reason: Core EMC-mediated process; supported by IMP of EMC subunits. Supporting Evidence: file:human/EMC6/EMC6-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 (structural) evidence placing EMC6 in the ER membrane. Core compartment. Reason: Experimentally supported core location. Supporting Evidence: file:human/EMC6/EMC6-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 (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. Reason: Core EMC-mediated process. Supporting Evidence: PMID:30415835 G protein-coupled receptors (GPCRs) |
| GO:0071816 tail-anchored membrane protein insertion into ER membrane | IMP PMID:29242231 The ER membrane protein complex is a transmembrane domain in... | ACCEPT | 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. Reason: Core EMC-mediated process; directly demonstrated. Supporting Evidence: PMID:29242231 tail-anchored membrane proteins with moderately hydrophobic transmembrane |
| GO:0000045 autophagosome assembly | IMP PMID:23182941 A novel ER-localized transmembrane protein, EMC6, interacts ... | KEEP AS NON CORE | 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. 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. Supporting Evidence: PMID:23182941 It was shown to regulate |
| GO:0005515 protein binding | IPI PMID:23182941 A novel ER-localized transmembrane protein, EMC6, interacts ... | KEEP AS NON CORE | 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. Reason: Real but peripheral interactions; bare protein binding is uninformative per guidelines. Supporting Evidence: PMID:23182941 interacts with RAB5A |
| GO:0005789 endoplasmic reticulum membrane | IDA PMID:23182941 A novel ER-localized transmembrane protein, EMC6, interacts ... | ACCEPT | Summary: Direct evidence that EMC6 is an ER-localized transmembrane protein. Core compartment. Reason: Experimentally supported core location. Supporting Evidence: PMID:23182941 ER-localized transmembrane protein |
| GO:1903349 omegasome membrane | IDA PMID:23182941 A novel ER-localized transmembrane protein, EMC6, interacts ... | KEEP AS NON CORE | 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. Reason: Experimentally reported but peripheral, tied to the (likely indirect) autophagy role; not the core localization. Supporting Evidence: PMID:23182941 colocalized with the omegasome marker ZFYVE1/DFCP1 |
| 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/EMC6/EMC6-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 EMC6 in the EMC by the foundational ERAD-network mapping study. Core structural identity. Reason: Core EMC membership; directly demonstrated. Supporting Evidence: file:human/EMC6/EMC6-uniprot.txt Component of the ER membrane protein complex (EMC). |
Loading supporting content…
Download this section (compressed HTML)Q: 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?
Q: 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?
Experiment: 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).
Experiment: 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.
Loading supporting content…
Download this section (compressed HTML)Loading supporting content…
Download this section (compressed HTML)Loading supporting content…
Download this section (compressed HTML)Loading supporting content…
Download this section (compressed HTML)