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.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0032977 membrane insertase activity | IBA GO_REF:0000033 | KEEP AS NON CORE | 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. 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. Supporting Evidence: file:human/EMC8/EMC8-uniprot.txt enables the energy-independent insertion into endoplasmic |
| GO:0045050 protein insertion into ER membrane by stop-transfer membrane-anchor sequence | IBA GO_REF:0000033 | ACCEPT | 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. 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. Supporting Evidence: file:human/EMC8/EMC8-uniprot.txt cotranslational insertion of multi-pass membrane proteins in which |
| GO:0071816 tail-anchored membrane protein insertion into ER membrane | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetic assignment of the EMC role in post-translational insertion of tail-anchored proteins; EMC8 participates as part of the complex. Reason: Consistent with experimental evidence that EMC is required for post-translational insertion of tail-anchored proteins into the ER membrane. Supporting Evidence: file:human/EMC8/EMC8-uniprot.txt post-translational insertion of tail-anchored/TA proteins in |
| GO:0072546 EMC complex | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetic assignment of EMC complex membership, the defining and core cellular-component association for EMC8. Reason: Core localization/membership for EMC8; directly demonstrated experimentally (IDA PMID:22119785; IPI PMID:32439656) and conserved across the EMC8/EMC9 family. Supporting Evidence: file:human/EMC8/EMC8-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 localization from the UniProt subcellular location, consistent with EMC8 being a peripheral, cytoplasmic-side subunit of the ER-resident EMC. Reason: Correct core compartment; EMC8 is a peripheral membrane protein at the ER membrane. Redundant with EXP/NAS ER membrane annotations. Supporting Evidence: file:human/EMC8/EMC8-uniprot.txt SUBCELLULAR LOCATION: Endoplasmic reticulum membrane |
| GO:0072546 EMC complex | IEA GO_REF:0000002 | ACCEPT | Summary: InterPro-based (IPR005366, EMC8/9 family) electronic assignment to the EMC complex, consistent with the experimental membership annotation. Reason: Correct core membership; redundant with IDA/IPI/IBA evidence for EMC complex membership. Supporting Evidence: file:human/EMC8/EMC8-uniprot.txt Component of the ER membrane protein complex (EMC) |
| GO:0005515 protein binding | IPI PMID:16189514 Towards a proteome-scale map of the human protein-protein in... | KEEP AS NON CORE | 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. 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. Supporting Evidence: file:human/EMC8/EMC8-uniprot.txt O43402; Q15006: EMC2; NbExp=17 |
| GO:0005515 protein binding | IPI PMID:22119785 Defining human ERAD networks through an integrative mapping ... | KEEP AS NON CORE | 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. Reason: Real, biologically meaningful interaction with the EMC2 scaffold, but the bare MF term is uninformative; the membership is better captured by GO:0072546. Supporting Evidence: file:human/EMC8/EMC8-uniprot.txt O43402; Q15006: EMC2; NbExp=17 |
| GO:0005515 protein binding | IPI PMID:26496610 A human interactome in three quantitative dimensions organiz... | KEEP AS NON CORE | Summary: EMC8-EMC2 interaction (WITH/FROM UniProtKB:Q15006) from a quantitative stoichiometry-resolved interactome. Bare protein binding is uninformative. Reason: Genuine EMC2 interaction from a high-throughput study, but bare protein binding is uninformative; intra-EMC contact captured by complex membership. Supporting Evidence: file:human/EMC8/EMC8-uniprot.txt O43402; Q15006: EMC2; NbExp=17 |
| GO:0005515 protein binding | IPI PMID:28514442 Architecture of the human interactome defines protein commun... | KEEP AS NON CORE | Summary: EMC8-EMC2 interaction (WITH/FROM UniProtKB:Q15006) from the BioPlex interactome/community analysis. Bare protein binding is uninformative. Reason: Real EMC2 interaction from a high-throughput AP-MS network, but bare protein binding is uninformative; not elevated to core. Supporting Evidence: file:human/EMC8/EMC8-uniprot.txt O43402; Q15006: EMC2; NbExp=17 |
| GO:0005515 protein binding | IPI PMID:30021884 Histone Interaction Landscapes Visualized by Crosslinking Ma... | KEEP AS NON CORE | 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. 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. Supporting Evidence: file:human/EMC8/EMC8-uniprot.txt O43402; Q15006: EMC2; NbExp=17 |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | KEEP AS NON CORE | Summary: EMC8-EMC2 interaction (WITH/FROM UniProtKB:Q15006) from the HuRI reference binary interactome. Bare protein binding is uninformative. Reason: Genuine binary EMC2 interaction, but bare protein binding is uninformative; complex membership captures the functional content. Supporting Evidence: file:human/EMC8/EMC8-uniprot.txt O43402; Q15006: EMC2; NbExp=17 |
| GO:0005515 protein binding | IPI PMID:32439656 Structural basis for membrane insertion by the human ER memb... | KEEP AS NON CORE | 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. Reason: Structurally corroborated EMC2 interaction, but bare protein binding is uninformative; the structural membership is captured by GO:0072546 EMC complex. Supporting Evidence: file:human/EMC8/EMC8-uniprot.txt O43402; Q15006: EMC2; NbExp=17 |
| GO:0005515 protein binding | IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling... | KEEP AS NON CORE | Summary: EMC8-EMC2 interaction (WITH/FROM UniProtKB:Q15006) from BioPlex 3 dual proteome-scale networks. Bare protein binding is uninformative. Reason: Real EMC2 interaction from a large AP-MS network, but bare protein binding is uninformative; not elevated to core. Supporting Evidence: file:human/EMC8/EMC8-uniprot.txt O43402; Q15006: EMC2; NbExp=17 |
| GO:0005515 protein binding | IPI PMID:35271311 OpenCell: Endogenous tagging for the cartography of human ce... | KEEP AS NON CORE | Summary: EMC8-EMC2 interaction (WITH/FROM UniProtKB:Q15006) from OpenCell endogenous-tagging interactome/localization. Bare protein binding is uninformative. Reason: Genuine endogenous EMC2 interaction, but bare protein binding is uninformative; the functional content is captured by EMC complex membership. Supporting Evidence: file:human/EMC8/EMC8-uniprot.txt O43402; Q15006: EMC2; NbExp=17 |
| GO:0005783 endoplasmic reticulum | IDA GO_REF:0000052 | ACCEPT | Summary: Direct immunofluorescence (HPA) evidence for ER localization, consistent with EMC8 being a subunit of the ER-resident EMC. Reason: Correct compartment; the more specific ER membrane (GO:0005789) better captures the peripheral, cytoplasmic-side association of EMC8. Supporting Evidence: file:human/EMC8/EMC8-uniprot.txt SUBCELLULAR LOCATION: Endoplasmic reticulum membrane |
| GO:0005789 endoplasmic reticulum membrane | NAS PMID:29242231 The ER membrane protein complex is a transmembrane domain in... | ACCEPT | Summary: ComplexPortal (NAS) assertion of EMC8 ER membrane localization, drawn from the EMC insertase characterization. Core compartment for EMC8. 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. Supporting Evidence: file:human/EMC8/EMC8-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: ComplexPortal IDA for the EMC role in cotranslational insertion of multipass proteins via stop-transfer anchors; EMC8 participates as part of the complex. Reason: Consistent with experimentally demonstrated EMC insertase function; a complex-level process EMC8 is involved in. Supporting Evidence: file:human/EMC8/EMC8-uniprot.txt cotranslational insertion of multi-pass membrane proteins in which |
| 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: 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. Reason: Directly supported by the reconstitution evidence that EMC inserts tail-anchored substrates; a complex-level process EMC8 is involved in. Supporting Evidence: file:human/EMC8/EMC8-uniprot.txt post-translational insertion of tail-anchored/TA proteins in |
| GO:0072546 EMC complex | IPI PMID:32439656 Structural basis for membrane insertion by the human ER memb... | ACCEPT | Summary: ComplexPortal IPI placing EMC8 in the EMC, corroborated by the cryo-EM structure of the human nine-subunit complex. Core membership. Reason: Core, structurally demonstrated EMC complex membership; EMC8 (chain H) is resolved in the human EMC structures. Supporting Evidence: file:human/EMC8/EMC8-uniprot.txt ComplexPortal; CPX-5848; Endoplasmic reticulum membrane complex, EMC8 variant. |
| GO:0005789 endoplasmic reticulum membrane | EXP PMID:22119785 Defining human ERAD networks through an integrative mapping ... | ACCEPT | Summary: Experimental localization of EMC8 (identified as COX4NB) to the ER membrane in the integrative ERAD/EMC mapping study. Core compartment. Reason: Core compartment supported by direct experimental evidence; EMC8 associates peripherally with the ER membrane as part of EMC. Supporting Evidence: PMID:22119785 we identified 5 additional HCIPs (TTC35, TMEM32/MMGT1, TMEM85, C15orf24 and COX4NB) |
| GO:0032977 membrane insertase activity | IMP PMID:29809151 The ER membrane protein complex interacts cotranslationally ... | KEEP AS NON CORE | 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. 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. Supporting Evidence: file:human/EMC8/EMC8-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... | KEEP AS NON CORE | 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. 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. Supporting Evidence: file:human/EMC8/EMC8-uniprot.txt the topology of multi-pass |
| 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: IMP evidence that EMC (including EMC8) is required for cotranslational insertion of multipass membrane proteins via stop-transfer anchors. Reason: Consistent with the experimentally supported EMC function; loss of EMC subunits impairs cotranslational multipass insertion. A complex-level process EMC8 is involved in. Supporting Evidence: file:human/EMC8/EMC8-uniprot.txt cotranslational insertion of multi-pass membrane proteins in which |
| 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 (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. Reason: Consistent with experimental topogenesis evidence; EMC mediates cotranslational insertion that sets multipass topology. A complex-level process EMC8 is involved in. Supporting Evidence: file:human/EMC8/EMC8-uniprot.txt the proper cotranslational insertion of N-terminal |
| GO:0016020 membrane | HDA PMID:19946888 Defining the membrane proteome of NK cells. | KEEP AS NON CORE | Summary: High-throughput membrane-proteome (NK-cell) MS dataset assigning generic membrane localization. Correct but a generic parent of the ER membrane localization. Reason: Accurate but low-information; the specific ER membrane (GO:0005789) better captures the localization of EMC8. Supporting Evidence: file:human/EMC8/EMC8-uniprot.txt SUBCELLULAR LOCATION: Endoplasmic reticulum membrane |
| GO:0005737 cytoplasm | IDA PMID:22119785 Defining human ERAD networks through an integrative mapping ... | KEEP AS NON CORE | 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. Reason: Correct (EMC8 is a peripheral, cytoplasmic-side subunit) but generic; the ER membrane localization and EMC complex membership are the informative core terms. Supporting Evidence: file:human/EMC8/EMC8-uniprot.txt Cytoplasmic side |
| GO:0072546 EMC complex | IDA PMID:22119785 Defining human ERAD networks through an integrative mapping ... | ACCEPT | 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. Reason: Core, directly demonstrated EMC complex membership; this is the defining cellular-component association for EMC8. Supporting Evidence: PMID:22119785 we identified 5 additional HCIPs (TTC35, TMEM32/MMGT1, TMEM85, C15orf24 and COX4NB) |
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Download this section (compressed HTML)Q: 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?
Q: Does the degenerate MPN domain of EMC8 retain any binding or regulatory function, or is it purely structural for incorporation into the complex?
Experiment: 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.
Experiment: 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.
Experiment: 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.
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