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.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0032977 membrane insertase activity | IBA GO_REF:0000033 | ACCEPT | 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. 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. Supporting Evidence: file:human/EMC2/EMC2-uniprot.txt enables the energy-independent insertion into endoplasmic |
| GO:0071816 tail-anchored membrane protein insertion into ER membrane | IBA GO_REF:0000033 | ACCEPT | 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. Reason: Core EMC-mediated process; the EMC post-translationally inserts tail-anchored proteins and EMC2 is a constitutive subunit. Supporting Evidence: file:human/EMC2/EMC2-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 across the EMC2 family, matching direct experimental and structural evidence. Core structural identity of EMC2. 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. Supporting Evidence: file:human/EMC2/EMC2-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 subcellular location from UniProt; EMC2 is a peripheral membrane protein on the cytosolic side of the ER membrane. Correct core compartment. Reason: Correct core location; redundant with experimental IDA evidence. Supporting Evidence: file:human/EMC2/EMC2-uniprot.txt SUBCELLULAR LOCATION: Endoplasmic reticulum membrane |
| 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 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. Reason: Genuine EMC subunit interactions but the bare protein binding term is uninformative per curation guidelines; EMC complex membership captures the informative content. Supporting Evidence: file:human/EMC2/EMC2-uniprot.txt Q15006; O43402: EMC8 |
| GO:0005515 protein binding | IPI PMID:22119785 Defining human ERAD networks through an integrative mapping ... | KEEP AS NON CORE | 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. Reason: Genuine EMC subunit interactions; bare protein binding is uninformative and not core. Supporting Evidence: file:human/EMC2/EMC2-uniprot.txt Q15006; Q9P0I2: EMC3 |
| GO:0005515 protein binding | IPI PMID:25416956 A proteome-scale map of the human interactome network. | KEEP AS NON CORE | Summary: High-throughput interactome (HuRI) captures of EMC2 with EMC9 and other partners (COX4NB, IKZF3). Bare protein binding is uninformative. Reason: High-throughput interactions, partly reflecting EMC partners; the bare term is uninformative and not core. Supporting Evidence: file:human/EMC2/EMC2-uniprot.txt Q15006; Q9Y3B6: EMC9 |
| GO:0005515 protein binding | IPI PMID:26496610 A human interactome in three quantitative dimensions organiz... | KEEP AS NON CORE | 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. Reason: Genuine EMC subunit interactions; bare protein binding is uninformative and not core. Supporting Evidence: file:human/EMC2/EMC2-uniprot.txt Q15006; O43402: EMC8 |
| GO:0005515 protein binding | IPI PMID:28514442 Architecture of the human interactome defines protein commun... | KEEP AS NON CORE | Summary: Interactome-communities study capturing EMC2 with EMC subunits EMC8, EMC9 and MMGT1/EMC5. Bare protein binding is uninformative. Reason: Genuine EMC subunit interactions; bare protein binding is uninformative and not core. Supporting Evidence: file:human/EMC2/EMC2-uniprot.txt Q15006; O43402: EMC8 |
| GO:0005515 protein binding | IPI PMID:30021884 Histone Interaction Landscapes Visualized by Crosslinking Ma... | KEEP AS NON CORE | 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. Reason: Likely incidental high-throughput capture with the EMC partner EMC8; bare protein binding is uninformative and not core. Supporting Evidence: file:human/EMC2/EMC2-uniprot.txt Q15006; O43402: EMC8 |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | KEEP AS NON CORE | Summary: High-throughput binary (HuRI) interactome capturing EMC2 with EMC8, EMC9 and several other proteins (SH3BP5L, HSP90B1, SS18L2, PCDHB12). Bare protein binding is uninformative. Reason: High-throughput binary interactions, partly EMC partners; bare protein binding is uninformative and not core. Supporting Evidence: file:human/EMC2/EMC2-uniprot.txt Q15006; O43402: EMC8 |
| GO:0005515 protein binding | IPI PMID:32439656 Structural basis for membrane insertion by the human ER memb... | KEEP AS NON CORE | Summary: Interaction evidence from the cryo-EM structural study of the human EMC (EMC2 with EMC8, EMC3, MMGT1/EMC5, EMC9), reflecting genuine intra-complex partnerships. Bare protein binding is uninformative. Reason: Structurally grounded intra-complex interactions; bare protein binding is uninformative and the EMC complex membership term captures the informative content. Supporting Evidence: file:human/EMC2/EMC2-uniprot.txt Q15006; Q9P0I2: EMC3 |
| GO:0005515 protein binding | IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling... | KEEP AS NON CORE | 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. Reason: High-throughput EMC subunit interactions; bare protein binding is uninformative and not core. Supporting Evidence: file:human/EMC2/EMC2-uniprot.txt Q15006; O43402: EMC8 |
| GO:0005515 protein binding | IPI PMID:35271311 OpenCell: Endogenous tagging for the cartography of human ce... | KEEP AS NON CORE | 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. Reason: High-throughput EMC subunit interactions; bare protein binding is uninformative and not core. Supporting Evidence: file:human/EMC2/EMC2-uniprot.txt Q15006; O43402: EMC8 |
| GO:0005515 protein binding | IPI PMID:40205054 Multimodal cell maps as a foundation for structural and func... | KEEP AS NON CORE | Summary: Multimodal cell-map interactome capturing EMC2 with the EMC subunit EMC3 (Q9P0I2). Genuine EMC partner but bare protein binding is uninformative. Reason: High-throughput EMC subunit interaction; bare protein binding is uninformative and not core. Supporting Evidence: file:human/EMC2/EMC2-uniprot.txt Q15006; Q9P0I2: EMC3 |
| GO:0005789 endoplasmic reticulum membrane | NAS PMID:29242231 The ER membrane protein complex is a transmembrane domain in... | ACCEPT | Summary: ComplexPortal NAS annotation of ER membrane localization for the EMC, consistent with experimental evidence and EMC2's peripheral association with the cytosolic face of the ER membrane. Reason: Correct core location; consistent with experimental IDA evidence. Supporting Evidence: file:human/EMC2/EMC2-uniprot.txt SUBCELLULAR LOCATION: Endoplasmic reticulum membrane |
| GO:0045050 protein insertion into ER membrane by stop-transfer membrane-anchor sequence | IDA PMID:29242231 The ER membrane protein complex is a transmembrane domain in... | ACCEPT | Summary: The EMC inserts transmembrane segments, including stop-transfer membrane-anchor sequences of multipass clients; EMC2 is a constitutive subunit of this insertase. Core complex-level process. Reason: Core EMC-mediated process; the EMC is a demonstrated transmembrane-domain insertase and EMC2 is its cytosolic scaffold. Supporting Evidence: PMID:29242231 transmembrane domain insertase |
| GO:0071816 tail-anchored membrane protein insertion into ER membrane | IDA PMID:29242231 The ER membrane protein complex is a transmembrane domain in... | ACCEPT | Summary: The EMC mediates post-translational insertion of tail-anchored proteins with moderately hydrophobic TMDs, demonstrated directly in this study; EMC2 is a constitutive subunit. Core complex-level process. Reason: Core EMC-mediated process; directly demonstrated for the complex. Supporting Evidence: PMID:29242231 tail-anchored membrane proteins with moderately hydrophobic transmembrane |
| GO:0072546 EMC complex | IPI PMID:32439656 Structural basis for membrane insertion by the human ER memb... | ACCEPT | Summary: ComplexPortal IPI assignment of EMC complex membership based on the cryo-EM structure of the human EMC. Core structural identity of EMC2 as the cytosolic TPR scaffold. Reason: Structurally demonstrated core EMC membership. Supporting Evidence: file:human/EMC2/EMC2-uniprot.txt Component of the ER membrane protein complex (EMC) |
| GO:0005515 protein binding | IPI PMID:33964204 WNK1 is an assembly factor for the human ER membrane protein... | KEEP AS NON CORE | 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. 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. Supporting Evidence: PMID:33964204 amphipathic helix to stabilize the soluble |
| GO:0045050 protein insertion into ER membrane by stop-transfer membrane-anchor sequence | IDA PMID:33964204 WNK1 is an assembly factor for the human ER membrane protein... | ACCEPT | 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. Reason: Core EMC-mediated process; EMC2 assembly is required for the insertase activity assayed in this study. Supporting Evidence: file:human/EMC2/EMC2-uniprot.txt stop-transfer membrane-anchor sequences become ER membrane spanning |
| GO:0072546 EMC complex | IDA PMID:33964204 WNK1 is an assembly factor for the human ER membrane protein... | ACCEPT | Summary: Direct demonstration that EMC2 is the architectural scaffold subunit of the EMC, anchoring both cytosolic and membrane-spanning subunits. Core structural identity. Reason: Core EMC membership; directly demonstrated, with EMC2 shown to be the scaffold of the complex. Supporting Evidence: PMID:33964204 superhelical architectural scaffold |
| GO:0032977 membrane insertase activity | IMP PMID:29809151 The ER membrane protein complex interacts cotranslationally ... | ACCEPT | 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). Reason: Complex-level MF correctly qualified contributes_to; EMC2 supports insertase activity as scaffold but is not catalytic. Supporting Evidence: file:human/EMC2/EMC2-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... | ACCEPT | 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. Reason: Complex-level MF correctly qualified contributes_to; EMC2 supports the insertase activity of the EMC. Supporting Evidence: file:human/EMC2/EMC2-uniprot.txt enables the energy-independent insertion into endoplasmic |
| GO:0045050 protein insertion into ER membrane by stop-transfer membrane-anchor sequence | IMP PMID:29809151 The ER membrane protein complex interacts cotranslationally ... | ACCEPT | Summary: The EMC is required for cotranslational insertion of multipass proteins in which stop-transfer membrane-anchor sequences become membrane-spanning helices; EMC2 is a constitutive subunit. Core EMC process. Reason: Core EMC-mediated process; supported by IMP of EMC subunits. Supporting Evidence: file:human/EMC2/EMC2-uniprot.txt stop-transfer membrane-anchor sequences become ER membrane spanning |
| GO:0005789 endoplasmic reticulum membrane | IDA PMID:22119785 Defining human ERAD networks through an integrative mapping ... | ACCEPT | Summary: Direct experimental ER membrane localization from the foundational ERAD-network mapping study that first identified the EMC. Core compartment for EMC2 (cytosolic face). Reason: Experimentally supported core location. Supporting Evidence: file:human/EMC2/EMC2-uniprot.txt SUBCELLULAR LOCATION: Endoplasmic reticulum membrane |
| GO:0042406 extrinsic component of endoplasmic reticulum membrane | IDA PMID:32439656 Structural basis for membrane insertion by the human ER memb... | ACCEPT | 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. Reason: Accurate and specific topological localization; EMC2 is a peripheral membrane protein on the cytoplasmic side of the ER membrane. Supporting Evidence: file:human/EMC2/EMC2-uniprot.txt Peripheral membrane protein |
| 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 (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. Reason: Core EMC-mediated process. Supporting Evidence: PMID:30415835 G protein-coupled receptors |
| GO:0005737 cytoplasm | IDA PMID:22119785 Defining human ERAD networks through an integrative mapping ... | KEEP AS NON CORE | 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. 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. Supporting Evidence: file:human/EMC2/EMC2-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 EMC2 in the EMC by the foundational ERAD-network mapping study. Core structural identity. Reason: Core EMC membership; directly demonstrated. Supporting Evidence: file:human/EMC2/EMC2-uniprot.txt Component of the ER membrane protein complex (EMC) |
| GO:0005783 endoplasmic reticulum | IDA PMID:10942595 A visual intracellular classification strategy for uncharact... | KEEP AS NON CORE | 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. Reason: Correct compartment but a parent of the more precise ER membrane / extrinsic-component terms; retained as supporting but non-core. Supporting Evidence: file:human/EMC2/EMC2-uniprot.txt SUBCELLULAR LOCATION: Endoplasmic reticulum membrane |
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Download this section (compressed HTML)Q: 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?
Q: Beyond WNK1, what other factors govern the stability and assembly checkpoint of orphan cytosolic EMC2, and how is this coupled to overall EMC stoichiometry?
Experiment: 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.
Experiment: 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.
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