id: Q9NPA0 gene_symbol: EMC7 product_type: PROTEIN status: COMPLETE taxon: id: NCBITaxon:9606 label: Homo sapiens description: EMC7 (ER membrane protein complex subunit 7) is a 242 aa single-pass type I ER membrane protein and a constitutive subunit of the ER membrane protein complex (EMC), a conserved transmembrane-domain insertase and membrane-protein chaperone of the endoplasmic reticulum. After cleavage of its N-terminal signal peptide, EMC7 presents a large lumenal beta-sandwich domain followed by a single transmembrane helix and a short, partly disordered cytoplasmic tail. EMC7 is a peripheral, non-catalytic architectural subunit; the catalytic insertase machinery (the membrane-embedded hydrophilic vestibule) is formed by EMC3 and EMC6. As part of the EMC, EMC7 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 contain destabilizing residues, including post-translational insertion of tail-anchored proteins and cotranslational insertion and topogenesis of multipass membrane proteins. EMC7 localizes to the ER membrane and is broadly expressed. existing_annotations: - term: id: GO:0072546 label: EMC complex evidence_type: IBA original_reference_id: GO_REF:0000033 qualifier: part_of review: summary: Phylogenetic assignment of EMC complex membership, consistent with direct experimental and structural identification of EMC7 in the EMC. This is the core structural identity of EMC7. action: ACCEPT reason: EMC complex membership is the core cellular-component identity of EMC7; supported by IDA, cryo-EM, and the conserved EMC7 family. supported_by: - reference_id: file:human/EMC7/EMC7-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 EMC7. action: ACCEPT reason: Correct core location; redundant with experimental EXP/IDA evidence. supported_by: - reference_id: file:human/EMC7/EMC7-uniprot.txt supporting_text: 'SUBCELLULAR LOCATION: Endoplasmic reticulum membrane' - term: id: GO:0030246 label: carbohydrate binding evidence_type: IEA original_reference_id: GO_REF:0000002 qualifier: enables review: summary: InterPro fold-homology assignment derived from the lumenal beta-sandwich resembling a starch-binding/carbohydrate-binding-like domain. There is no experimental evidence that EMC7 binds carbohydrate; the fold is structural and the assignment is an over-propagated electronic inference. action: MARK_AS_OVER_ANNOTATED reason: Fold-similarity-only IEA with no supporting evidence that EMC7 actually binds carbohydrate; the beta-sandwich is structural and serves complex architecture. supported_by: - reference_id: file:human/EMC7/EMC7-uniprot.txt supporting_text: Starch-binding domain-like - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:28514442 qualifier: enables review: summary: High-throughput interactome capture (with PDIA4). Bare protein binding is uninformative. action: KEEP_AS_NON_CORE reason: High-throughput interaction; bare protein binding is uninformative per guidelines. supported_by: - reference_id: file:human/EMC7/EMC7-uniprot.txt supporting_text: 'P13667: PDIA4' - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:28734904 qualifier: enables review: summary: Interaction with WLS (Wntless), itself an EMC client, identified in a Wntless-interactome screen. The interaction plausibly reflects EMC client engagement, but bare protein binding is uninformative. action: KEEP_AS_NON_CORE reason: Likely reflects client engagement, but the bare term is uninformative and not core. supported_by: - reference_id: file:human/EMC7/EMC7-uniprot.txt supporting_text: 'Q5T9L3-1: WLS' - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:31286866 qualifier: enables review: summary: Interaction with WLS from a Wntless splicing/PPI study. WLS is an EMC client; bare protein binding is uninformative. action: KEEP_AS_NON_CORE reason: Likely client engagement; bare term uninformative, not core. supported_by: - reference_id: file:human/EMC7/EMC7-uniprot.txt supporting_text: 'Q5T9L3-1: WLS' - 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 (CYSRT1, NOTCH2NLC, keratin-associated proteins, MEOX2); several are likely sticky Y2H hits. Bare protein binding is uninformative. action: KEEP_AS_NON_CORE reason: High-throughput binary interactions of uncertain biological relevance; bare term uninformative. supported_by: - reference_id: file:human/EMC7/EMC7-uniprot.txt supporting_text: 'A8MQ03: CYSRT1' - 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 PDIA4). Bare protein binding is uninformative. action: KEEP_AS_NON_CORE reason: High-throughput interaction; bare term uninformative, not core. supported_by: - reference_id: file:human/EMC7/EMC7-uniprot.txt supporting_text: 'P13667: PDIA4' - 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. Core compartment. action: ACCEPT reason: Correct core location; consistent with EXP/IDA evidence. supported_by: - reference_id: file:human/EMC7/EMC7-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; EMC7 participates as an EMC subunit. A genuine EMC-mediated process, though EMC7 is non-catalytic. action: ACCEPT reason: Correct EMC-mediated process EMC7 is involved in as a complex subunit; non-core relative to complex membership. 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; EMC7 participates as an EMC subunit. Genuine EMC-mediated process. action: ACCEPT reason: Correct EMC-mediated process EMC7 participates in via membership. 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 EMC7. action: ACCEPT reason: Structurally demonstrated core EMC membership. supported_by: - reference_id: file:human/EMC7/EMC7-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/EMC7/EMC7-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 that EMC subunit depletion impairs membrane insertion; EMC7 contributes_to the complex insertase activity. The qualifier is appropriate, but as a peripheral lumenal subunit EMC7's role is via complex participation, not standalone catalysis. action: KEEP_AS_NON_CORE reason: Whole-complex molecular function to which EMC7 contributes; EMC7 is non-catalytic (the EMC3/EMC6 vestibule is the catalytic core), so not EMC7's own core MF. supported_by: - reference_id: file:human/EMC7/EMC7-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 EMC7 contributes as a complex subunit. Non-core for the non-catalytic EMC7. action: KEEP_AS_NON_CORE reason: Whole-complex MF; EMC7 contributes via membership but is not the catalytic subunit. supported_by: - reference_id: file:human/EMC7/EMC7-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; EMC7 participates as a subunit. Genuine EMC process. action: ACCEPT reason: Correct EMC-mediated process EMC7 participates in. supported_by: - reference_id: file:human/EMC7/EMC7-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 EMC7 in the ER membrane. Core compartment. action: ACCEPT reason: Experimentally supported core location. supported_by: - reference_id: file:human/EMC7/EMC7-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; EMC7 participates as a subunit. Genuine EMC process. action: ACCEPT reason: Correct EMC-mediated process EMC7 participates in. supported_by: - reference_id: PMID:30415835 supporting_text: G protein-coupled receptors (GPCRs) - 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/EMC7/EMC7-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 EMC7 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/EMC7/EMC7-uniprot.txt supporting_text: Component of the ER membrane protein complex (EMC). - term: id: GO:0016020 label: membrane evidence_type: NAS original_reference_id: PMID:12975309 qualifier: located_in review: summary: Generic membrane localization asserted (NAS) in the secreted-protein discovery initiative bioinformatics survey that first catalogued this transmembrane protein. Correct but generic and superseded by the specific ER membrane localization. action: KEEP_AS_NON_CORE reason: Correct but generic and based on a bioinformatic transmembrane prediction; the ER membrane term is the informative localization. supported_by: - reference_id: file:human/EMC7/EMC7-uniprot.txt supporting_text: Single-pass type I membrane protein 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 EMC7 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: PMID:12975309 title: 'The secreted protein discovery initiative (SPDI), a large-scale effort to identify novel human secreted and transmembrane proteins: a bioinformatics assessment.' findings: [] reference_review: relevance: LOW correctness: VERIFIED review_notes: Bioinformatic transmembrane-protein survey; source of a generic NAS membrane annotation. - id: PMID:22119785 title: Defining human ERAD networks through an integrative mapping strategy. findings: - statement: Affinity-MS ERAD-network mapping that identified the EMC (including EMC7) 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 membership and ER membrane localization for EMC7. - id: PMID:28514442 title: Architecture of the human interactome defines protein communities and disease networks. findings: [] reference_review: relevance: LOW correctness: VERIFIED review_notes: High-throughput interactome (PDIA4 partner); bare protein binding. - id: PMID:28734904 title: Identifying novel members of the Wntless interactome through genetic and candidate gene approaches. findings: [] reference_review: relevance: LOW correctness: VERIFIED review_notes: WLS (Wntless, an EMC client) interaction; plausibly client engagement. - 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. reference_section_type: ABSTRACT reference_review: relevance: HIGH correctness: VERIFIED review_notes: Establishes the EMC insertase function; basis for insertion BP 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 GPCR/multipass first TMDs, initiating accurate topogenesis. reference_section_type: ABSTRACT reference_review: relevance: HIGH correctness: VERIFIED review_notes: Topogenesis role of the EMC. - id: PMID:31286866 title: Alternative splicing of the Wnt trafficking protein, Wntless and its effects on protein-protein interactions. findings: [] reference_review: relevance: LOW correctness: VERIFIED review_notes: WLS interaction; plausibly EMC client engagement. - id: PMID:32296183 title: A reference map of the human binary protein interactome. findings: [] reference_review: relevance: LOW correctness: VERIFIED review_notes: HuRI binary interactome; several likely sticky Y2H hits (keratin-associated proteins). - 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; EMC7 is a single-pass type I subunit with a large lumenal domain; the catalytic vestibule is formed by EMC3 and EMC6. reference_section_type: ABSTRACT reference_review: relevance: HIGH correctness: VERIFIED review_notes: Structural placement of EMC7 and topology; 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 interactome (PDIA4 partner); bare protein binding. - id: PMID:35287476 title: The Function, Structure, and Origins of the ER Membrane Protein Complex. findings: - statement: Authoritative review of EMC function, structure, and evolution; places EMC7 as a single-pass subunit contributing a transmembrane helix and cytosolic loops to the dynamic front subdomain near the EMC3/EMC6 catalytic vestibule. reference_section_type: LITERATURE_REVIEW reference_review: relevance: MEDIUM correctness: VERIFIED review_notes: PubMed-verified (Annu Rev Biochem 2022). Review synthesizing EMC architecture and mechanism; supports the structural placement and non-catalytic role of EMC7 already described in the review. - id: PMID:37199759 title: A selectivity filter in the ER membrane protein complex limits protein misinsertion at the ER. findings: - statement: EMC7 is experimentally confirmed as a type I single-pass subunit and contributes conserved hydrophobic cytosolic loops (and a C-terminal amphipathic helix) beneath the EMC hydrophilic vestibule that transiently capture substrate TMDs; EMC7 is required for biogenesis of the tail-anchored client squalene synthase (SQS). reference_section_type: ABSTRACT reference_review: relevance: HIGH correctness: VERIFIED review_notes: PubMed-verified (J Cell Biol 2023, PMID:37199759). Provides EMC7-specific mechanistic evidence for a substrate-capture/selectivity-filter role and confirms type I single-pass topology and SQS-client dependence. - id: PMID:37957425 title: EMC rectifies the topology of multipass membrane proteins. findings: - statement: The EMC post-translationally rectifies the topology of multipass membrane proteins by inserting terminal/C-terminal TMDs after release from the ribosome-Sec61 complex, a mechanism estimated to apply to ~250 diverse human multipass proteins; EMC7 participates as an EMC subunit. reference_section_type: ABSTRACT reference_review: relevance: MEDIUM correctness: VERIFIED review_notes: PubMed-verified (Nat Struct Mol Biol 2024, PMID:37957425). Expands the set of EMC-dependent processes (post-translational topology rectification) in which EMC7-containing complexes participate; complex-level, not EMC7-specific catalysis. - id: PMID:32111841 title: Selective EMC subunits act as molecular tethers of intracellular organelles exploited during viral entry. findings: - statement: EMC7 (with EMC4) acts as an ER-late endosome tether supporting SV40 polyomavirus delivery to the ER; EMC7's cytosolic C-terminal tail binds the late-endosomal GTPase Rab7 and EMC7/EMC4 bind the ER SNARE syntaxin-18, and EMC7 depletion blocks SV40 infection. reference_section_type: RESULTS reference_review: relevance: MEDIUM correctness: VERIFIED review_notes: PubMed-verified (Nat Commun 2020, PMID:32111841). Non-canonical EMC7-specific role in organelle tethering (ER-endosome contact) and viral entry, mediated by the cytosolic tail binding Rab7 and syntaxin-18. - id: PMID:38517390 title: Structural insights into human EMC and its interaction with VDAC. findings: - statement: Cryo-EM of human EMC apo and VDAC1-bound states; EMC7's transmembrane helix becomes ordered upon VDAC1 binding and contributes a substantial fraction (~one-third) of the EMC-VDAC1 interface at mitochondria-ER contact sites. reference_section_type: RESULTS reference_review: relevance: MEDIUM correctness: VERIFIED review_notes: PubMed-verified (Aging (Albany NY) 2024, PMID:38517390). Structural evidence that EMC7's TMH mediates the EMC-VDAC1 interaction at ER-mitochondria contact sites; supports a conformationally plastic, interface-forming role for EMC7. - id: file:human/EMC7/EMC7-uniprot.txt title: UniProt entry Q9NPA0 (EMC7_HUMAN), ER membrane protein complex subunit 7 findings: - statement: Single-pass type I ER membrane EMC subunit with a lumenal beta-sandwich domain; non-catalytic; part of the EMC insertase. reference_section_type: OTHER core_functions: - description: Constitutive architectural subunit of the ER membrane protein complex (EMC), contributing as a complex member 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/EMC7/EMC7-uniprot.txt supporting_text: Component of the ER membrane protein complex (EMC). - reference_id: PMID:29242231 supporting_text: EMC is a transmembrane domain insertase 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: [] suggested_questions: - question: What specific structural or functional contribution does the lumenal beta-sandwich domain of EMC7 make to EMC stability or substrate handling? - question: Are the EMC7-WLS interactions reported in interactome screens a reflection of EMC client engagement rather than a standalone binding function? suggested_experiments: - description: Test whether the EMC7 lumenal beta-sandwich domain binds any carbohydrate ligand in vitro to confirm or refute the InterPro-derived carbohydrate-binding annotation. - description: Reconstitute EMC complexes lacking EMC7 to assess its contribution to complex assembly, stability, and insertion efficiency of representative tail-anchored and multipass substrates.