id: Q15006
gene_symbol: EMC2
product_type: PROTEIN
status: COMPLETE
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: EMC2 (ER membrane protein complex subunit 2; also TTC35/tetratricopeptide repeat protein 35) is a 297-residue, all-alpha-helical tetratricopeptide-repeat (TPR) protein that is the soluble cytosolic scaffold subunit of the ER membrane protein complex (EMC), a conserved nine- to ten-subunit transmembrane-domain insertase and chaperone of the endoplasmic reticulum. Its superhelical TPR solenoid organizes the cytosolic face of the EMC, forming an extensive hydrophobic interface with the mutually exclusive paralogous subunits EMC8/EMC9 and contacting the cytosolic extensions of the membrane-spanning subunits EMC3 and EMC5; in this way EMC2 anchors and stabilizes both the cytosolic and the membrane-embedded portions of the complex. EMC2 itself is non-catalytic and contains no transmembrane domain; it is a peripheral membrane protein bound to the cytoplasmic side of the ER membrane via the other EMC subunits. As part of the EMC it contributes to the energy-independent insertion of newly synthesized membrane proteins into the ER membrane, including post-translational insertion of tail-anchored proteins and cotranslational insertion and N-exo topogenesis of multipass membrane proteins such as G protein-coupled receptors; the catalytic insertion vestibule is formed by EMC3 and EMC6. Unassembled cytosolic EMC2 is recognized and degraded by the ubiquitin-proteasome system, and its assembly into the EMC is promoted by the kinase WNK1, which shields the EMC2-EMC8 interface. EMC2 is broadly expressed and resides at the ER membrane.
existing_annotations:
- term:
    id: GO:0032977
    label: membrane insertase activity
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: contributes_to
  review:
    summary: Phylogenetic (PAN-GO) assignment of membrane insertase activity to the conserved EMC2 family, carried with the contributes_to qualifier. EMC2 is the non-catalytic cytosolic scaffold of the EMC; the catalytic insertion vestibule is formed by EMC3 and EMC6, so contributes_to (rather than enables) is the appropriate framing.
    action: ACCEPT
    reason: Complex-level molecular function correctly qualified contributes_to; EMC2 supports the insertase activity of the whole complex as its architectural scaffold without being catalytic itself.
    supported_by:
    - reference_id: file:human/EMC2/EMC2-uniprot.txt
      supporting_text: enables the energy-independent insertion into endoplasmic
- term:
    id: GO:0071816
    label: tail-anchored membrane protein insertion into ER membrane
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: Phylogenetic propagation of the EMC's tail-anchored protein insertion role across the EMC2 family, consistent with direct experimental EMC evidence. Core complex-level biological process to which EMC2 contributes as scaffold.
    action: ACCEPT
    reason: Core EMC-mediated process; the EMC post-translationally inserts tail-anchored proteins and EMC2 is a constitutive subunit.
    supported_by:
    - reference_id: file:human/EMC2/EMC2-uniprot.txt
      supporting_text: post-translational insertion of tail-anchored/TA proteins in
- 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 across the EMC2 family, matching direct experimental and structural evidence. Core structural identity of EMC2.
    action: ACCEPT
    reason: EMC complex membership is the core cellular-component identity of EMC2 and is supported by IDA, cryo-EM/crystal structures, and the conserved EMC2 family.
    supported_by:
    - reference_id: file:human/EMC2/EMC2-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; EMC2 is a peripheral membrane protein on the cytosolic side of the ER membrane. Correct core compartment.
    action: ACCEPT
    reason: Correct core location; redundant with experimental IDA evidence.
    supported_by:
    - reference_id: file:human/EMC2/EMC2-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Endoplasmic reticulum membrane'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:16189514
  qualifier: enables
  review:
    summary: High-throughput proteome-scale interaction map capturing EMC2 interactions with the EMC subunits EMC8 (O43402) and EMC9 (Q9Y3B6). These are bona fide intra-complex partners, but bare protein binding is uninformative and not elevated to core.
    action: KEEP_AS_NON_CORE
    reason: Genuine EMC subunit interactions but the bare protein binding term is uninformative per curation guidelines; EMC complex membership captures the informative content.
    supported_by:
    - reference_id: file:human/EMC2/EMC2-uniprot.txt
      supporting_text: 'Q15006; O43402: EMC8'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:22119785
  qualifier: enables
  review:
    summary: Interactions from the foundational ERAD-network mapping study that first defined the EMC, capturing EMC2 with EMC subunits EMC8, EMC3 (Q9P0I2), EMC9 and MMGT1/EMC5. Real intra-complex partnerships, but bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: Genuine EMC subunit interactions; bare protein binding is uninformative and not core.
    supported_by:
    - reference_id: file:human/EMC2/EMC2-uniprot.txt
      supporting_text: 'Q15006; Q9P0I2: EMC3'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:25416956
  qualifier: enables
  review:
    summary: High-throughput interactome (HuRI) captures of EMC2 with EMC9 and other partners (COX4NB, IKZF3). Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: High-throughput interactions, partly reflecting EMC partners; the bare term is uninformative and not core.
    supported_by:
    - reference_id: file:human/EMC2/EMC2-uniprot.txt
      supporting_text: 'Q15006; Q9Y3B6: EMC9'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:26496610
  qualifier: enables
  review:
    summary: Quantitative (stoichiometry-resolved) interactome capturing EMC2 with EMC subunits EMC8, EMC3 and MMGT1/EMC5. Real intra-complex partnerships, but bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: Genuine EMC subunit interactions; bare protein binding is uninformative and not core.
    supported_by:
    - reference_id: file:human/EMC2/EMC2-uniprot.txt
      supporting_text: 'Q15006; O43402: EMC8'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:28514442
  qualifier: enables
  review:
    summary: Interactome-communities study capturing EMC2 with EMC subunits EMC8, EMC9 and MMGT1/EMC5. Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: Genuine EMC subunit interactions; bare protein binding is uninformative and not core.
    supported_by:
    - reference_id: file:human/EMC2/EMC2-uniprot.txt
      supporting_text: 'Q15006; O43402: EMC8'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:30021884
  qualifier: enables
  review:
    summary: Histone-interaction crosslinking-MS study in intact nuclei capturing EMC2 with EMC8 (O43402). The recovery is most plausibly incidental (nuclear-envelope contamination); bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: Likely incidental high-throughput capture with the EMC partner EMC8; bare protein binding is uninformative and not core.
    supported_by:
    - reference_id: file:human/EMC2/EMC2-uniprot.txt
      supporting_text: 'Q15006; O43402: EMC8'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:32296183
  qualifier: enables
  review:
    summary: High-throughput binary (HuRI) interactome capturing EMC2 with EMC8, EMC9 and several other proteins (SH3BP5L, HSP90B1, SS18L2, PCDHB12). Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: High-throughput binary interactions, partly EMC partners; bare protein binding is uninformative and not core.
    supported_by:
    - reference_id: file:human/EMC2/EMC2-uniprot.txt
      supporting_text: 'Q15006; O43402: EMC8'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:32439656
  qualifier: enables
  review:
    summary: Interaction evidence from the cryo-EM structural study of the human EMC (EMC2 with EMC8, EMC3, MMGT1/EMC5, EMC9), reflecting genuine intra-complex partnerships. Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: Structurally grounded intra-complex interactions; bare protein binding is uninformative and the EMC complex membership term captures the informative content.
    supported_by:
    - reference_id: file:human/EMC2/EMC2-uniprot.txt
      supporting_text: 'Q15006; Q9P0I2: EMC3'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:33961781
  qualifier: enables
  review:
    summary: BioPlex affinity-MS interactome capturing EMC2 with EMC subunits EMC8, EMC3, MMGT1/EMC5 and EMC9. Genuine EMC partners but bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: High-throughput EMC subunit interactions; bare protein binding is uninformative and not core.
    supported_by:
    - reference_id: file:human/EMC2/EMC2-uniprot.txt
      supporting_text: 'Q15006; O43402: EMC8'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:35271311
  qualifier: enables
  review:
    summary: OpenCell endogenous-tagging interactome capturing EMC2 with EMC subunits EMC8, EMC3, MMGT1/EMC5 and EMC9. Real EMC partners but bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: High-throughput EMC subunit interactions; bare protein binding is uninformative and not core.
    supported_by:
    - reference_id: file:human/EMC2/EMC2-uniprot.txt
      supporting_text: 'Q15006; O43402: EMC8'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:40205054
  qualifier: enables
  review:
    summary: Multimodal cell-map interactome capturing EMC2 with the EMC subunit EMC3 (Q9P0I2). Genuine EMC partner but bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: High-throughput EMC subunit interaction; bare protein binding is uninformative and not core.
    supported_by:
    - reference_id: file:human/EMC2/EMC2-uniprot.txt
      supporting_text: 'Q15006; Q9P0I2: EMC3'
- 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 and EMC2's peripheral association with the cytosolic face of the ER membrane.
    action: ACCEPT
    reason: Correct core location; consistent with experimental IDA evidence.
    supported_by:
    - reference_id: file:human/EMC2/EMC2-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 segments, including stop-transfer membrane-anchor sequences of multipass clients; EMC2 is a constitutive subunit of this insertase. Core complex-level process.
    action: ACCEPT
    reason: Core EMC-mediated process; the EMC is a demonstrated transmembrane-domain insertase and EMC2 is its cytosolic scaffold.
    supported_by:
    - reference_id: PMID:29242231
      supporting_text: 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 with moderately hydrophobic TMDs, demonstrated directly in this study; EMC2 is a constitutive subunit. Core complex-level process.
    action: ACCEPT
    reason: Core EMC-mediated process; directly demonstrated for the complex.
    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 EMC2 as the cytosolic TPR scaffold.
    action: ACCEPT
    reason: Structurally demonstrated core EMC membership.
    supported_by:
    - reference_id: file:human/EMC2/EMC2-uniprot.txt
      supporting_text: Component of the ER membrane protein complex (EMC)
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:33964204
  qualifier: enables
  review:
    summary: Curated interaction (WITH/FROM WNK1, Q9H4A3) from the study showing that WNK1 uses an amphipathic helix to stabilize soluble EMC2 by binding the EMC2-EMC8 interface, preventing its ubiquitination and permitting EMC assembly. This is a biologically meaningful assembly interaction, but the GO term itself (bare protein binding) is uninformative.
    action: KEEP_AS_NON_CORE
    reason: Captures the functionally important WNK1 assembly-factor interaction, but bare protein binding is uninformative per curation guidelines; the regulatory significance is recorded in the description and notes rather than elevated to a core MF.
    supported_by:
    - reference_id: PMID:33964204
      supporting_text: amphipathic helix to stabilize the soluble
- term:
    id: GO:0045050
    label: protein insertion into ER membrane by stop-transfer membrane-anchor sequence
  evidence_type: IDA
  original_reference_id: PMID:33964204
  qualifier: involved_in
  review:
    summary: The WNK1/EMC-assembly study assays EMC-dependent insertion of stop-transfer membrane-anchor clients; EMC2 is the cytosolic scaffold whose assembly is required for this complex activity. Core complex-level process.
    action: ACCEPT
    reason: Core EMC-mediated process; EMC2 assembly is required for the insertase activity assayed in this study.
    supported_by:
    - reference_id: file:human/EMC2/EMC2-uniprot.txt
      supporting_text: stop-transfer membrane-anchor sequences become ER membrane spanning
- term:
    id: GO:0072546
    label: EMC complex
  evidence_type: IDA
  original_reference_id: PMID:33964204
  qualifier: part_of
  review:
    summary: Direct demonstration that EMC2 is the architectural scaffold subunit of the EMC, anchoring both cytosolic and membrane-spanning subunits. Core structural identity.
    action: ACCEPT
    reason: Core EMC membership; directly demonstrated, with EMC2 shown to be the scaffold of the complex.
    supported_by:
    - reference_id: PMID:33964204
      supporting_text: superhelical architectural scaffold
- term:
    id: GO:0032977
    label: membrane insertase activity
  evidence_type: IMP
  original_reference_id: PMID:29809151
  qualifier: contributes_to
  review:
    summary: IMP evidence (cotranslational multipass biogenesis study) that the EMC has membrane insertase activity, to which EMC2 contributes as the cytosolic scaffold. The contributes_to qualifier is appropriate because EMC2 is non-catalytic (the vestibule is EMC3/EMC6).
    action: ACCEPT
    reason: Complex-level MF correctly qualified contributes_to; EMC2 supports insertase activity as scaffold but is not catalytic.
    supported_by:
    - reference_id: file:human/EMC2/EMC2-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 EMC2 contributes as the cytosolic scaffold subunit. contributes_to correctly reflects that EMC2 is non-catalytic.
    action: ACCEPT
    reason: Complex-level MF correctly qualified contributes_to; EMC2 supports the insertase activity of the EMC.
    supported_by:
    - reference_id: file:human/EMC2/EMC2-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; EMC2 is a constitutive subunit. Core EMC process.
    action: ACCEPT
    reason: Core EMC-mediated process; supported by IMP of EMC subunits.
    supported_by:
    - reference_id: file:human/EMC2/EMC2-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:22119785
  qualifier: located_in
  review:
    summary: Direct experimental ER membrane localization from the foundational ERAD-network mapping study that first identified the EMC. Core compartment for EMC2 (cytosolic face).
    action: ACCEPT
    reason: Experimentally supported core location.
    supported_by:
    - reference_id: file:human/EMC2/EMC2-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Endoplasmic reticulum membrane'
- term:
    id: GO:0042406
    label: extrinsic component of endoplasmic reticulum membrane
  evidence_type: IDA
  original_reference_id: PMID:32439656
  qualifier: located_in
  review:
    summary: Direct (structural) evidence that EMC2 is a peripheral/extrinsic membrane protein on the cytosolic face of the ER membrane, consistent with its lack of a transmembrane domain and its TPR-scaffold association with membrane subunits. An informative, accurate localization for EMC2.
    action: ACCEPT
    reason: Accurate and specific topological localization; EMC2 is a peripheral membrane protein on the cytoplasmic side of the ER membrane.
    supported_by:
    - reference_id: file:human/EMC2/EMC2-uniprot.txt
      supporting_text: Peripheral membrane protein
- 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 evidence (topogenesis study) that the EMC inserts stop-transfer membrane-anchor sequences and sets the N-exo topology of multipass clients such as GPCRs; EMC2 is part of the insertase. Core EMC process.
    action: ACCEPT
    reason: Core EMC-mediated process.
    supported_by:
    - reference_id: PMID:30415835
      supporting_text: G protein-coupled receptors
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IDA
  original_reference_id: PMID:22119785
  qualifier: located_in
  review:
    summary: Direct cytoplasm localization from the EMC-discovery study, consistent with EMC2 being the cytosolic/peripheral subunit of the EMC and detectable as a soluble protein. A generic parent of the more informative ER membrane / extrinsic-component terms.
    action: KEEP_AS_NON_CORE
    reason: Correct but generic; the extrinsic-component-of-ER-membrane and ER membrane terms capture the informative localization. Per guidelines an experimental IDA is retained, not removed.
    supported_by:
    - reference_id: file:human/EMC2/EMC2-uniprot.txt
      supporting_text: Cytoplasmic side
- term:
    id: GO:0072546
    label: EMC complex
  evidence_type: IDA
  original_reference_id: PMID:22119785
  qualifier: part_of
  review:
    summary: Direct experimental identification of EMC2 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/EMC2/EMC2-uniprot.txt
      supporting_text: Component of the ER membrane protein complex (EMC)
- term:
    id: GO:0005783
    label: endoplasmic reticulum
  evidence_type: IDA
  original_reference_id: PMID:10942595
  qualifier: located_in
  review:
    summary: Early GFP-fusion localization screen (PROLOC) that localized EMC2/TTC35 (KIAA0103) to the endoplasmic reticulum, predating the EMC understanding. Correct but a generic parent of the specific ER membrane term.
    action: KEEP_AS_NON_CORE
    reason: Correct compartment but a parent of the more precise ER membrane / extrinsic-component terms; retained as supporting but non-core.
    supported_by:
    - reference_id: file:human/EMC2/EMC2-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Endoplasmic reticulum membrane'
core_functions:
- description: Constitutive cytosolic TPR scaffold subunit of the ER membrane protein complex (EMC); its superhelical solenoid anchors and stabilizes both the cytosolic (EMC8/EMC9) and membrane-spanning (EMC3, EMC5) subunits, organizing the complex and contributing to its energy-independent membrane insertase activity.
  contributes_to_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: PMID:33964204
    supporting_text: superhelical architectural scaffold
  - reference_id: file:human/EMC2/EMC2-uniprot.txt
    supporting_text: enables the energy-independent insertion into endoplasmic
- description: As part of the EMC, contributes to post-translational insertion of tail-anchored proteins and cotranslational insertion and N-exo topogenesis of multipass membrane proteins (including GPCRs) at the ER membrane.
  contributes_to_molecular_function:
    id: GO:0032977
    label: membrane insertase activity
  locations:
  - id: GO:0005789
    label: endoplasmic reticulum membrane
  supported_by:
  - reference_id: file:human/EMC2/EMC2-uniprot.txt
    supporting_text: post-translational insertion of tail-anchored/TA proteins in
  - reference_id: PMID:37957425
    supporting_text: TMDs near the carboxyl terminus of mammalian multipass proteins are inserted post-translationally by the endoplasmic reticulum membrane protein complex (EMC)
  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: []
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
      EMC2 as a constitutive EMC subunit.'
- 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:10942595
  title: A visual intracellular classification strategy for uncharacterized human proteins.
  findings:
  - statement: GFP-fusion localization screen that localized EMC2/TTC35 (KIAA0103) to the endoplasmic reticulum.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: Early GFP-fusion localization screen predating the EMC understanding; source of the IDA ER localization. Abstract-only context.
- id: PMID:16189514
  title: Towards a proteome-scale map of the human protein-protein interaction network.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: High-throughput Y2H interactome; source of IPI protein-binding partners that include the EMC subunits EMC8/EMC9.
- 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 EMC2) in human cells and localized it to the ER membrane/cytoplasm.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Foundational identification of the human EMC; source of EMC complex membership and ER membrane/cytoplasm localization for EMC2.
- id: PMID:25416956
  title: A proteome-scale map of the human interactome network.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: High-throughput interactome; source of IPI protein-binding partners (including the EMC subunit EMC9).
- id: PMID:26496610
  title: A human interactome in three quantitative dimensions organized by stoichiometries and abundances.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: Quantitative interactome; source of IPI protein-binding partners that are EMC subunits (EMC8, EMC3, MMGT1/EMC5).
- id: PMID:28514442
  title: Architecture of the human interactome defines protein communities and disease networks.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: Interactome-communities study; source of IPI protein-binding partners that are EMC subunits.
- 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 with moderately hydrophobic TMDs.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Establishes the insertase function of the EMC; basis for the insertion BP/MF 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: HIGH
    correctness: VERIFIED
    review_notes: Cotranslational multipass biogenesis role of the EMC; basis for the IMP MF/BP annotations.
- id: PMID:30021884
  title: Histone Interaction Landscapes Visualized by Crosslinking Mass Spectrometry in Intact Cell Nuclei.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: Histone crosslinking-MS in nuclei; the EMC2-EMC8 capture is most plausibly incidental (nuclear-envelope contamination).
- id: PMID:30415835
  title: EMC Is Required to Initiate Accurate Membrane Protein Topogenesis.
  findings:
  - statement: The EMC sets the N-exo topology of the first TMD of GPCRs and other multipass proteins, initiating accurate topogenesis.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Topogenesis/orientation role of the EMC; GPCR clients; basis for IMP MF/BP annotations.
- id: PMID:32296183
  title: A reference map of the human binary protein interactome.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: High-throughput HuRI binary interactome; source of several IPI protein-binding partners (including EMC subunits).
- 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; substrate insertion occurs via an enclosed hydrophilic vestibule formed by EMC3 and EMC6, and EMC2 mutagenesis identifies its interfaces with EMC5/EMC3/EMC8.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Structural basis for the EMC; confirms EMC2 as the cytosolic scaffold and maps its subunit interfaces. 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 affinity-MS interactome; source of IPI protein-binding annotations with EMC subunits.
- id: PMID:33964204
  title: WNK1 is an assembly factor for the human ER membrane protein complex.
  findings:
  - statement: EMC2 is the superhelical architectural scaffold of the EMC, organized around the soluble EMC2-EMC8/9 heterodimer and anchoring both cytosolic and membrane-spanning subunits.
    reference_section_type: ABSTRACT
  - statement: WNK1 uses a conserved amphipathic helix to stabilize soluble EMC2 by binding the EMC2-EMC8 interface, preventing its ubiquitination and permitting EMC assembly.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Defines EMC2 as the cytosolic architectural scaffold and the WNK1-dependent assembly/stability mechanism; source of the IDA EMC-membership and scaffold-related annotations.
- id: PMID:35271311
  title: 'OpenCell: Endogenous tagging for the cartography of human cellular organization.'
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: OpenCell endogenous-tagging interactome; source of IPI protein-binding annotations with EMC subunits.
- id: PMID:40205054
  title: Multimodal cell maps as a foundation for structural and functional genomics.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: Multimodal cell-map interactome; source of an IPI protein-binding annotation with the EMC subunit EMC3.
- id: file:human/EMC2/EMC2-uniprot.txt
  title: UniProt entry Q15006 (EMC2_HUMAN), ER membrane protein complex subunit 2
  findings:
  - statement: Cytosolic TPR-scaffold subunit of the EMC; peripheral membrane protein on the cytoplasmic side of the ER membrane; unassembled EMC2 is ubiquitinated and degraded, and WNK1 promotes its assembly.
    reference_section_type: OTHER
- id: PMID:37199759
  title: A selectivity filter in the ER membrane protein complex limits protein misinsertion
    at the ER.
  findings:
  - statement: The EMC inserts tail-anchored substrates via a hydrophilic vestibule whose positively charged entrance acts as a charge-repulsion selectivity filter; deletion of the EMC4 cytosolic EMC2-binding site impairs biogenesis of a canonical EMC-dependent tail-anchored client (SQS/FDFT1), underscoring the functional importance of EMC2-mediated cytosolic assembly interfaces.
    reference_section_type: RESULTS
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: PubMed-verified (J Cell Biol 2023, 222:e202212007). Refines the EMC insertion/selectivity mechanism and shows the EMC2-binding interface (via EMC4) is required for client biogenesis, supporting EMC2's architectural scaffold role.
- id: PMID:37957425
  title: EMC rectifies the topology of multipass membrane proteins.
  findings:
  - statement: The EMC mediates post-translational insertion of C-terminal transmembrane domains of multipass membrane proteins (e.g. SOAT1) to rectify their topology after ribosome release; this sequential co-/post-translational mechanism may apply to ~250 diverse multipass proteins, expanding the EMC client scope.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: PubMed-verified (Nat Struct Mol Biol 2024, 31:32-41). Defines a post-translational EMC topology-rectification activity broadening the EMC (and thus EMC2 scaffold) client repertoire; complex-level mechanism.
- id: PMID:40753078
  title: The EMC acts as a chaperone for membrane proteins.
  findings:
  - statement: Beyond its insertase activity, the EMC has a chaperone mode that engages client transmembrane domains (via the EMC1 subunit) and modulates their orientation in the lipid bilayer; the authors build a machine-learning client predictor, establishing the EMC as a multifunctional membrane-protein biogenesis machine.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: PubMed-verified (Nat Commun 2025, 16:7097). Establishes an EMC chaperone function distinct from insertion; complex-level and primarily attributed to EMC1, but relevant context for EMC2 as the cytosolic scaffold of the same complex.
suggested_questions:
- question: How does the EMC2 TPR scaffold transmit conformational information between the cytosolic EMC2-EMC8/9 module and the membrane-embedded EMC3/EMC6 insertase vestibule during substrate insertion?
- question: Beyond WNK1, what other factors govern the stability and assembly checkpoint of orphan cytosolic EMC2, and how is this coupled to overall EMC stoichiometry?
suggested_experiments:
- description: Reconstitute the human EMC with wild-type versus interface-mutant EMC2 (e.g. R28A, E156A, R227A) in proteoliposomes and measure insertion of tail-anchored and multipass substrates to quantify the scaffold's contribution to insertase activity versus complex assembly.
- description: Use quantitative proteomics and cycloheximide-chase in WNK1-depleted versus control cells to define how WNK1 loss destabilizes EMC2, the EMC, and downstream membrane-protein clients.