id: Q5UCC4 gene_symbol: EMC10 product_type: PROTEIN status: COMPLETE taxon: id: NCBITaxon:9606 label: Homo sapiens description: EMC10 (ER membrane protein complex subunit 10; also C19orf63, INM02) is a 262 aa single-pass type I ER membrane glycoprotein with a cleavable N-terminal signal peptide, a large lumenal domain (N-glycosylated at Asn-182), a single transmembrane helix, and a short cytoplasmic tail. It is a constitutive lumenal/peripheral subunit of the ER membrane protein complex (EMC), a conserved transmembrane-domain insertase and membrane-protein chaperone that mediates energy-independent insertion of newly synthesized membrane proteins into the ER membrane, including post-translational insertion of tail-anchored proteins and cotranslational insertion and topogenesis of multipass membrane proteins such as G protein-coupled receptors. The membrane insertase activity resides in the EMC3/EMC6 membrane core; EMC10 is a non-catalytic structural subunit whose bulk projects into the ER lumen. An alternatively spliced isoform is secreted (HSS1) and circulates; secreted EMC10 has been characterized as a bone marrow-derived angiogenic growth factor that stimulates endothelial cell migration and outgrowth and promotes tissue repair after myocardial infarction. Biallelic loss-of-function variants in EMC10 cause a neurodevelopmental disorder with dysmorphic facies and variable seizures. EMC10 is broadly expressed, with the membrane form localizing to the ER membrane. alternative_products: - name: 1 (HSM1 {ECO:0000303|PubMed:20680400}) id: Q5UCC4-1 - name: 2 (Hematopoietic signal peptide-containing secreted) id: Q5UCC4-2 sequence_note: VSP_030473 existing_annotations: - term: id: GO:0072546 label: EMC complex evidence_type: IBA original_reference_id: GO_REF:0000033 qualifier: part_of review: summary: EMC10 is a constitutive subunit of the ER membrane protein complex; phylogenetic assignment is consistent with direct experimental and structural evidence. Core structural identity. action: ACCEPT reason: EMC complex membership is the core cellular-component identity of EMC10; supported by IDA, cryo-EM, and the conserved EMC10 family. supported_by: - reference_id: file:human/EMC10/EMC10-uniprot.txt supporting_text: Component of the ER membrane protein complex (EMC). - term: id: GO:0005576 label: extracellular region evidence_type: IEA original_reference_id: GO_REF:0000044 qualifier: located_in review: summary: Electronic transfer of the secreted (extracellular) localization from UniProt, reflecting the secreted isoform 2 (HSS1). Genuine but peripheral to the core EMC ER membrane role. action: KEEP_AS_NON_CORE reason: Real secreted-isoform localization but peripheral to the core EMC insertase function. supported_by: - reference_id: file:human/EMC10/EMC10-uniprot.txt supporting_text: '[Isoform 2]: Secreted' - 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 of the membrane isoform from UniProt; the correct and core compartment for EMC10. action: ACCEPT reason: Correct core location; redundant with experimental IDA evidence. supported_by: - reference_id: file:human/EMC10/EMC10-uniprot.txt supporting_text: '[Isoform 1]: Endoplasmic reticulum membrane' - term: id: GO:0005789 label: endoplasmic reticulum membrane evidence_type: NAS original_reference_id: PMID:29242231 qualifier: located_in review: summary: NAS annotation of ER membrane localization for the EMC, consistent with experimental evidence and the core compartment of EMC10. action: ACCEPT reason: Correct core location; consistent with EXP/IDA evidence. supported_by: - reference_id: file:human/EMC10/EMC10-uniprot.txt supporting_text: '[Isoform 1]: 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; EMC10 participates as a structural subunit. A genuine EMC whole-complex process. action: KEEP_AS_NON_CORE reason: Correct EMC process but complex-level; EMC10 is a lumenal/structural subunit contributing via membership rather than catalysis. supported_by: - reference_id: file:human/EMC10/EMC10-uniprot.txt supporting_text: stop-transfer membrane-anchor sequences become ER membrane spanning - 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; EMC10 participates as a structural subunit. A genuine EMC whole-complex process. action: KEEP_AS_NON_CORE reason: Correct EMC process but complex-level; EMC10's contribution is via membership. supported_by: - reference_id: file:human/EMC10/EMC10-uniprot.txt supporting_text: post-translational insertion of tail- - term: id: GO:0072546 label: EMC complex evidence_type: IPI original_reference_id: PMID:32439656 qualifier: part_of review: summary: ComplexPortal/structural IPI assignment of EMC complex membership based on the cryo-EM structure of the human EMC. Core structural identity. action: ACCEPT reason: Structurally demonstrated core EMC membership. supported_by: - reference_id: file:human/EMC10/EMC10-uniprot.txt supporting_text: Component of the ER membrane protein complex (EMC). - term: id: GO:0005576 label: extracellular region evidence_type: EXP original_reference_id: PMID:19570817 qualifier: located_in review: summary: INM02 (EMC10) is detectable in human serum; experimental secreted-form localization. Peripheral to the EMC's core ER membrane role. action: KEEP_AS_NON_CORE reason: Real secreted-form observation but peripheral to the core EMC insertase function. supported_by: - reference_id: file:human/EMC10/EMC10-uniprot.txt supporting_text: Present in serum - term: id: GO:0005576 label: extracellular region evidence_type: EXP original_reference_id: PMID:20680400 qualifier: located_in isoform: Q5UCC4-2 review: summary: The alternatively spliced isoform 2 (HSS1) is secreted; experimental evidence of a secreted form. Genuine but isoform-specific and peripheral to the EMC's core ER membrane role. action: KEEP_AS_NON_CORE reason: Real secreted isoform but peripheral to the core EMC insertase function and specific to isoform 2. supported_by: - reference_id: file:human/EMC10/EMC10-uniprot.txt supporting_text: '[Isoform 2]: Secreted' - term: id: GO:0005576 label: extracellular region evidence_type: EXP original_reference_id: PMID:28931551 qualifier: located_in review: summary: Secreted EMC10 acts as an extracellular angiogenic growth factor after myocardial infarction. Genuine secreted localization, peripheral to the core EMC role. action: KEEP_AS_NON_CORE reason: Real secreted-form observation but peripheral to the core EMC insertase function. supported_by: - reference_id: file:human/EMC10/EMC10-uniprot.txt supporting_text: '[Isoform 2]: Secreted' - 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; EMC10 contributes to the complex-level insertase activity but is not the catalytic subunit (the EMC3/EMC6 core is catalytic). action: KEEP_AS_NON_CORE reason: contributes_to is appropriate at complex level; not EMC10's standalone enzymatic core MF, as it is a lumenal/structural subunit. supported_by: - reference_id: file:human/EMC10/EMC10-uniprot.txt supporting_text: 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 EMC10 contributes as a structural subunit. action: KEEP_AS_NON_CORE reason: contributes_to is appropriate at complex level; not EMC10's standalone enzymatic core MF. supported_by: - reference_id: file:human/EMC10/EMC10-uniprot.txt supporting_text: 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; EMC10 participates as a subunit. action: KEEP_AS_NON_CORE reason: Correct EMC process but complex-level; EMC10's contribution is via membership. supported_by: - reference_id: file:human/EMC10/EMC10-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 EMC10 in the ER membrane. Core compartment. action: ACCEPT reason: Experimentally supported core location. supported_by: - reference_id: file:human/EMC10/EMC10-uniprot.txt supporting_text: '[Isoform 1]: 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; EMC10 participates as a subunit. action: KEEP_AS_NON_CORE reason: Correct EMC process but complex-level; EMC10's contribution is via membership. supported_by: - reference_id: file:human/EMC10/EMC10-uniprot.txt supporting_text: stop-transfer membrane-anchor sequences become ER membrane spanning - term: id: GO:0001938 label: positive regulation of endothelial cell proliferation evidence_type: IDA original_reference_id: PMID:28931551 qualifier: involved_in review: summary: Secreted EMC10 promotes endothelial cell outgrowth/proliferation in angiogenic assays. A genuine secreted-form moonlighting function, peripheral to the EMC insertase role. action: KEEP_AS_NON_CORE reason: Real secreted-form activity but peripheral to the core EMC function. supported_by: - reference_id: file:human/EMC10/EMC10-uniprot.txt supporting_text: Stimulates cardiac endothelial cell migration and outgrowth - term: id: GO:0010595 label: positive regulation of endothelial cell migration evidence_type: ISS original_reference_id: GO_REF:0000024 qualifier: involved_in review: summary: Secreted EMC10 stimulates cardiac endothelial cell migration via p38 MAPK/PAK/MK2 signaling. A genuine secreted-form moonlighting function, peripheral to the EMC insertase role. action: KEEP_AS_NON_CORE reason: Real secreted-form activity but peripheral to the core EMC function. supported_by: - reference_id: file:human/EMC10/EMC10-uniprot.txt supporting_text: Stimulates cardiac endothelial cell migration and outgrowth - term: id: GO:0045766 label: positive regulation of angiogenesis evidence_type: IMP original_reference_id: PMID:28931551 qualifier: involved_in review: summary: Loss/gain-of-function evidence that secreted EMC10 promotes angiogenesis and tissue repair after myocardial infarction. A genuine secreted-form moonlighting function, peripheral to the EMC insertase role. action: KEEP_AS_NON_CORE reason: Experimentally supported but pertains to the secreted form and is peripheral to the core EMC function. supported_by: - reference_id: file:human/EMC10/EMC10-uniprot.txt supporting_text: Promotes angiogenesis and tissue repair in the heart - 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/EMC10/EMC10-uniprot.txt supporting_text: '[Isoform 1]: 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 EMC10 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/EMC10/EMC10-uniprot.txt supporting_text: Component of the ER membrane protein complex (EMC). core_functions: - description: Constitutive lumenal/peripheral subunit of the ER membrane protein complex (EMC), localizing to the ER membrane and contributing to the EMC-mediated insertion and biogenesis of membrane proteins. molecular_function: id: GO:0005198 label: structural molecule activity in_complex: id: GO:0072546 label: EMC complex locations: - id: GO:0005789 label: endoplasmic reticulum membrane supported_by: - reference_id: file:human/EMC10/EMC10-uniprot.txt supporting_text: Component of the ER membrane protein complex (EMC). 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 EMC10 as a constitutive EMC subunit.' - id: GO_REF:0000024 title: Manual transfer of experimentally-verified manual GO annotation data to orthologs by curator judgment of sequence similarity 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:19570817 title: 'Molecular cloning of a novel secreted peptide, INM02, and regulation of its expression by glucose.' findings: - statement: INM02 (EMC10) is detectable in human serum and is glucose-regulated in islets. reference_section_type: ABSTRACT reference_review: relevance: MEDIUM correctness: VERIFIED review_notes: Characterizes the secreted INM02/EMC10 form; abstract-only in cache. - id: PMID:20680400 title: 'hHSS1: a novel secreted factor and suppressor of glioma growth located at chromosome 19q13.33.' findings: - statement: Describes the secreted HSS1 isoform and the membrane HSM1 isoform of EMC10; HSS1 suppresses glioma growth. reference_section_type: ABSTRACT reference_review: relevance: MEDIUM correctness: VERIFIED review_notes: Source of the secreted isoform 2 (HSS1) localization. - 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 EMC10) 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 EMC10. - id: PMID:28931551 title: EMC10 (Endoplasmic Reticulum Membrane Protein Complex Subunit 10) Is a Bone Marrow-Derived Angiogenic Growth Factor Promoting Tissue Repair After Myocardial Infarction. findings: - statement: Secreted EMC10 is a bone marrow-derived angiogenic growth factor that stimulates endothelial cell migration and outgrowth via p38 MAPK/PAK/MK2 and promotes tissue repair after myocardial infarction. reference_section_type: ABSTRACT reference_review: relevance: MEDIUM correctness: VERIFIED review_notes: Establishes the secreted-form angiogenic moonlighting function; peripheral to the core EMC role. Abstract-only in cache. - id: PMID:29242231 title: The ER membrane protein complex is a transmembrane domain insertase. findings: - statement: EMC is a transmembrane domain insertase mediating tail-anchored and stop-transfer insertion. reference_section_type: ABSTRACT reference_review: relevance: HIGH correctness: VERIFIED review_notes: Establishes the insertase function of the EMC; EMC10 participates as a structural subunit. - id: PMID:29809151 title: The ER membrane protein complex interacts cotranslationally to enable biogenesis of multipass membrane proteins. findings: [] 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: [] reference_review: relevance: MEDIUM correctness: VERIFIED review_notes: Topogenesis/orientation role of the EMC. - 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, with EMC10's lumenal domain resolved; defines the signal peptide and Asn-182 glycosylation. reference_section_type: ABSTRACT reference_review: relevance: HIGH correctness: VERIFIED review_notes: Structural basis for the EMC and EMC10 topology; abstract-only in cache. - id: PMID:37196677 title: 'EMC chaperone-Ca(V) structure reveals an ion channel assembly intermediate.' findings: - statement: Cryo-EM structures of the EMC bound to a CaV1.2 channel assembly intermediate reveal EMC transmembrane and cytoplasmic client-docking sites and a holdase/chaperone mode; the lumenal module (EMC1/EMC4/EMC7/EMC10) shifts during client engagement. reference_section_type: ABSTRACT reference_review: relevance: MEDIUM correctness: VERIFIED review_notes: PubMed-verified (Nature 2023, 619:410-419). First EMC-client structure; supports an EMC holdase/chaperone function and places EMC10 in the lumenal module that moves on client binding. EMC-level (not EMC10-specific) mechanism. - id: PMID:37199759 title: A selectivity filter in the ER membrane protein complex limits protein misinsertion at the ER. findings: - statement: Using an improved human EMC structural model, positively charged residues at the entrance of the hydrophilic vestibule act as a charge-based selectivity filter that rejects mitochondrial TA proteins and enforces the positive-inside rule; the model includes EMC7/EMC10 single-pass topology. reference_section_type: ABSTRACT reference_review: relevance: MEDIUM correctness: VERIFIED review_notes: PubMed-verified (J Cell Biol 2023, 222:8). EMC selectivity-filter mechanism; uses an improved EMC model that depicts EMC10 single-TMD topology. EMC-level mechanism, not EMC10 catalytic. - id: PMID:38517390 title: Structural insights into human EMC and its interaction with VDAC. findings: - statement: Cryo-EM apo- and VDAC-bound human EMC structures identify a gating plug within the hydrophilic vestibule and a conserved EMC-VDAC interaction at mitochondria-ER contact sites; in the VDAC1-bound state the EMC is unlikely to act as an insertase, indicating state-dependent functional switching. reference_section_type: ABSTRACT reference_review: relevance: MEDIUM correctness: VERIFIED review_notes: PubMed-verified (Aging (Albany NY) 2024, 16:5501-5525). Adds EMC conformational/functional states and an EMC-VDAC contact-site role; EMC-complex-level, not EMC10-specific. suggested_questions: - question: Is the secreted/angiogenic activity of EMC10 mechanistically independent of its EMC insertase role, and does the NEDDFAS neurodevelopmental phenotype arise from loss of EMC-mediated membrane protein biogenesis, loss of the secreted factor, or both? - question: What is the structural contribution of EMC10's lumenal domain to EMC stability and substrate handling? suggested_experiments: - description: Separate the membrane (EMC) and secreted (HSS1) functions using isoform-specific or domain-targeted knock-ins, and assess effects on EMC client biogenesis versus angiogenesis/endothelial signaling. - description: Define the EMC10-dependent client repertoire by quantitative membrane proteomics in EMC10-deficient versus rescued neurons to connect the molecular EMC defect to the NEDDFAS phenotype.