EMC10

UniProt ID: Q5UCC4
Organism: Homo sapiens
Review Status: COMPLETE
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Gene 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.

Existing Annotations Review

GO Term Evidence Action Reason
GO:0072546 EMC complex
IBA
GO_REF:0000033 		ACCEPT
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.
Reason: EMC complex membership is the core cellular-component identity of EMC10; supported by IDA, cryo-EM, and the conserved EMC10 family.
Supporting Evidence:
file:human/EMC10/EMC10-uniprot.txt
Component of the ER membrane protein complex (EMC).
GO:0005576 extracellular region
IEA
GO_REF:0000044 		KEEP AS NON CORE
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.
Reason: Real secreted-isoform localization but peripheral to the core EMC insertase function.
Supporting Evidence:
file:human/EMC10/EMC10-uniprot.txt
[Isoform 2]: Secreted
GO:0005789 endoplasmic reticulum membrane
IEA
GO_REF:0000044 		ACCEPT
Summary: Electronic transfer of the ER membrane subcellular location of the membrane isoform from UniProt; the correct and core compartment for EMC10.
Reason: Correct core location; redundant with experimental IDA evidence.
Supporting Evidence:
file:human/EMC10/EMC10-uniprot.txt
[Isoform 1]: Endoplasmic reticulum membrane
GO:0005789 endoplasmic reticulum membrane
NAS
PMID:29242231
The ER membrane protein complex is a transmembrane domain in... 		ACCEPT
Summary: NAS annotation of ER membrane localization for the EMC, consistent with experimental evidence and the core compartment of EMC10.
Reason: Correct core location; consistent with EXP/IDA evidence.
Supporting Evidence:
file:human/EMC10/EMC10-uniprot.txt
[Isoform 1]: 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... 		KEEP AS NON CORE
Summary: The EMC inserts transmembrane domains including stop-transfer membrane-anchor sequences; EMC10 participates as a structural subunit. A genuine EMC whole-complex process.
Reason: Correct EMC process but complex-level; EMC10 is a lumenal/structural subunit contributing via membership rather than catalysis.
Supporting Evidence:
file:human/EMC10/EMC10-uniprot.txt
stop-transfer membrane-anchor sequences become ER membrane spanning
GO:0071816 tail-anchored membrane protein insertion into ER membrane
IDA
PMID:29242231
The ER membrane protein complex is a transmembrane domain in... 		KEEP AS NON CORE
Summary: The EMC mediates post-translational insertion of tail-anchored proteins; EMC10 participates as a structural subunit. A genuine EMC whole-complex process.
Reason: Correct EMC process but complex-level; EMC10's contribution is via membership.
Supporting Evidence:
file:human/EMC10/EMC10-uniprot.txt
post-translational insertion of tail-
GO:0072546 EMC complex
IPI
PMID:32439656
Structural basis for membrane insertion by the human ER memb... 		ACCEPT
Summary: ComplexPortal/structural IPI assignment of EMC complex membership based on the cryo-EM structure of the human EMC. Core structural identity.
Reason: Structurally demonstrated core EMC membership.
Supporting Evidence:
file:human/EMC10/EMC10-uniprot.txt
Component of the ER membrane protein complex (EMC).
GO:0005576 extracellular region
EXP
PMID:19570817
Molecular cloning of a novel secreted peptide, INM02, and re... 		KEEP AS NON CORE
Summary: INM02 (EMC10) is detectable in human serum; experimental secreted-form localization. Peripheral to the EMC's core ER membrane role.
Reason: Real secreted-form observation but peripheral to the core EMC insertase function.
Supporting Evidence:
file:human/EMC10/EMC10-uniprot.txt
Present in serum
GO:0005576 extracellular region
EXP
Q5UCC4-2
PMID:20680400
hHSS1: a novel secreted factor and suppressor of glioma grow... 		KEEP AS NON CORE
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.
Reason: Real secreted isoform but peripheral to the core EMC insertase function and specific to isoform 2.
Supporting Evidence:
file:human/EMC10/EMC10-uniprot.txt
[Isoform 2]: Secreted
GO:0005576 extracellular region
EXP
PMID:28931551
EMC10 (Endoplasmic Reticulum Membrane Protein Complex Subuni... 		KEEP AS NON CORE
Summary: Secreted EMC10 acts as an extracellular angiogenic growth factor after myocardial infarction. Genuine secreted localization, peripheral to the core EMC role.
Reason: Real secreted-form observation but peripheral to the core EMC insertase function.
Supporting Evidence:
file:human/EMC10/EMC10-uniprot.txt
[Isoform 2]: Secreted
GO:0032977 membrane insertase activity
IMP
PMID:29809151
The ER membrane protein complex interacts cotranslationally ... 		KEEP AS NON CORE
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).
Reason: contributes_to is appropriate at complex level; not EMC10's standalone enzymatic core MF, as it is a lumenal/structural subunit.
Supporting Evidence:
file:human/EMC10/EMC10-uniprot.txt
energy-independent insertion into endoplasmic
GO:0032977 membrane insertase activity
IMP
PMID:30415835
EMC Is Required to Initiate Accurate Membrane Protein Topoge... 		KEEP AS NON CORE
Summary: IMP evidence (topogenesis study) supporting the EMC's membrane insertase activity, to which EMC10 contributes as a structural subunit.
Reason: contributes_to is appropriate at complex level; not EMC10's standalone enzymatic core MF.
Supporting Evidence:
file:human/EMC10/EMC10-uniprot.txt
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 ... 		KEEP AS NON CORE
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.
Reason: Correct EMC process but complex-level; EMC10's contribution is via membership.
Supporting Evidence:
file:human/EMC10/EMC10-uniprot.txt
stop-transfer membrane-anchor sequences become ER membrane spanning
GO:0005789 endoplasmic reticulum membrane
IDA
PMID:32439656
Structural basis for membrane insertion by the human ER memb... 		ACCEPT
Summary: Direct (structural) evidence placing EMC10 in the ER membrane. Core compartment.
Reason: Experimentally supported core location.
Supporting Evidence:
file:human/EMC10/EMC10-uniprot.txt
[Isoform 1]: Endoplasmic reticulum membrane
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... 		KEEP AS NON CORE
Summary: IMP (topogenesis study) supporting the EMC's role in insertion of stop-transfer membrane-anchor sequences; EMC10 participates as a subunit.
Reason: Correct EMC process but complex-level; EMC10's contribution is via membership.
Supporting Evidence:
file:human/EMC10/EMC10-uniprot.txt
stop-transfer membrane-anchor sequences become ER membrane spanning
GO:0001938 positive regulation of endothelial cell proliferation
IDA
PMID:28931551
EMC10 (Endoplasmic Reticulum Membrane Protein Complex Subuni... 		KEEP AS NON CORE
Summary: Secreted EMC10 promotes endothelial cell outgrowth/proliferation in angiogenic assays. A genuine secreted-form moonlighting function, peripheral to the EMC insertase role.
Reason: Real secreted-form activity but peripheral to the core EMC function.
Supporting Evidence:
file:human/EMC10/EMC10-uniprot.txt
Stimulates cardiac endothelial cell migration and outgrowth
GO:0010595 positive regulation of endothelial cell migration
ISS
GO_REF:0000024 		KEEP AS NON CORE
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.
Reason: Real secreted-form activity but peripheral to the core EMC function.
Supporting Evidence:
file:human/EMC10/EMC10-uniprot.txt
Stimulates cardiac endothelial cell migration and outgrowth
GO:0045766 positive regulation of angiogenesis
IMP
PMID:28931551
EMC10 (Endoplasmic Reticulum Membrane Protein Complex Subuni... 		KEEP AS NON CORE
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.
Reason: Experimentally supported but pertains to the secreted form and is peripheral to the core EMC function.
Supporting Evidence:
file:human/EMC10/EMC10-uniprot.txt
Promotes angiogenesis and tissue repair in the heart
GO:0016020 membrane
IDA
PMID:22119785
Defining human ERAD networks through an integrative mapping ... 		KEEP AS NON CORE
Summary: Direct generic membrane localization from the EMC-discovery study; a parent of the specific ER membrane term.
Reason: Correct but generic; the ER membrane term captures the informative localization.
Supporting Evidence:
file:human/EMC10/EMC10-uniprot.txt
[Isoform 1]: Endoplasmic reticulum membrane
GO:0072546 EMC complex
IDA
PMID:22119785
Defining human ERAD networks through an integrative mapping ... 		ACCEPT
Summary: Direct experimental identification of EMC10 in the EMC by the foundational ERAD-network mapping study. Core structural identity.
Reason: Core EMC membership; directly demonstrated.
Supporting Evidence:
file:human/EMC10/EMC10-uniprot.txt
Component of the ER membrane protein complex (EMC).

Core Functions

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:
structural molecule activity
Cellular Locations:
endoplasmic reticulum membrane
In Complex:
EMC complex
Supporting Evidence:
  • file:human/EMC10/EMC10-uniprot.txt
    Component of the ER membrane protein complex (EMC).

References

PMID:32459176
The architecture of EMC reveals a path for membrane protein insertion.
GO_REF:0000024
Manual transfer of experimentally-verified manual GO annotation data to orthologs by curator judgment of sequence similarity
GO_REF:0000033
Annotation inferences using phylogenetic trees
GO_REF:0000044
Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location vocabulary mapping, accompanied by conservative changes to GO terms applied by UniProt
PMID:19570817
Molecular cloning of a novel secreted peptide, INM02, and regulation of its expression by glucose.
  • INM02 (EMC10) is detectable in human serum and is glucose-regulated in islets.
PMID:20680400
hHSS1: a novel secreted factor and suppressor of glioma growth located at chromosome 19q13.33.
  • Describes the secreted HSS1 isoform and the membrane HSM1 isoform of EMC10; HSS1 suppresses glioma growth.
PMID:22119785
Defining human ERAD networks through an integrative mapping strategy.
  • Affinity-MS ERAD-network mapping that first identified the EMC (including EMC10) and localized it to the ER membrane.
PMID:28931551
EMC10 (Endoplasmic Reticulum Membrane Protein Complex Subunit 10) Is a Bone Marrow-Derived Angiogenic Growth Factor Promoting Tissue Repair After Myocardial Infarction.
  • 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.
PMID:29242231
The ER membrane protein complex is a transmembrane domain insertase.
  • EMC is a transmembrane domain insertase mediating tail-anchored and stop-transfer insertion.
PMID:29809151
The ER membrane protein complex interacts cotranslationally to enable biogenesis of multipass membrane proteins.
PMID:30415835
EMC Is Required to Initiate Accurate Membrane Protein Topogenesis.
PMID:32439656
Structural basis for membrane insertion by the human ER membrane protein complex.
  • Cryo-EM structure of the human EMC, with EMC10's lumenal domain resolved; defines the signal peptide and Asn-182 glycosylation.
PMID:37196677
EMC chaperone-Ca(V) structure reveals an ion channel assembly intermediate.
  • 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.
PMID:37199759
A selectivity filter in the ER membrane protein complex limits protein misinsertion at the ER.
  • 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.
PMID:38517390
Structural insights into human EMC and its interaction with VDAC.
  • 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.

Suggested Questions for Experts

Q: 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?

Q: What is the structural contribution of EMC10's lumenal domain to EMC stability and substrate handling?

Suggested Experiments

Experiment: 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.

Experiment: 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.

Deep Research

Falcon

(EMC10-deep-research-falcon.md)
this with annotations you find in gene/protein databases, but these can be outdated or inaccurate. Falcon Edison Scientific Literature 25 citations 2 artifacts 2026-06-12T02:18:46.944753
Edison artifact artifact-00 (text/markdown)
## Context ID: pqac-00000014 Figure 3A on page 5 provides an improved cryo-EM model of the human EMC, illustrating the transmembrane topology of its subunits. T (image/png)

The research report should be a detailed narrative explaining the function, biological processes, and localization of the gene product. Citations should be given for all claims.

You should prioritize authoritative reviews and primary scientific literature when conducting research. You can supplement
this with annotations you find in gene/protein databases, but these can be outdated or inaccurate.

We are specifically interested in the primary function of the gene - for enzymes, what reaction is catalyzed, and what is the substrate specificity? For transporters, what is the substrate? For structural proteins or adapters, what is the broader structural role? For signaling molecules, what is the role in the pathway.

We are interested in where in or outside the cell the gene product carries out its function.

We are also interested in the signaling or biochemical pathways in which the gene functions. We are less interested in broad pleiotropic effects, except where these elucidate the precise role.

Include evidence where possible. We are interested in both experimental evidence as well as inference from structure, evolution, or bioinformatic analysis. Precise studies should be prioritized over high-throughput, where available.

Research Report: Human EMC10 (UniProt Q5UCC4) — Functional Annotation and Biological Context

Executive summary

Human EMC10 encodes ER membrane protein complex subunit 10, a single-pass, ER-associated protein that forms part of the endoplasmic reticulum membrane protein complex (EMC), a conserved membrane-protein biogenesis machine that facilitates insertion/topogenesis and quality control of select membrane-protein transmembrane domains (TMDs). Structural work places EMC10 in the ER-lumenal module of the complex (with EMC1/EMC4/EMC7), with a flexible single TMD that is not part of the catalytic insertase core. Separately, multiple studies report secreted/soluble EMC10-related products (notably HSS1/EMC10-2) with paracrine signaling activities in cancer and cardiac repair contexts. Recent 2023–2024 cryo-EM studies significantly advanced mechanistic understanding of EMC function and conformational states, providing the most current framework for interpreting EMC10’s role. (pleiner2020structuralbasisfor pages 1-3, volkmar2020squaringtheemc pages 10-11, pleiner2023aselectivityfilter pages 1-2, chen2023emcchaperone–cavstructure pages 1-3, li2024structuralinsightsinto pages 1-3)

1) Target identity verification (critical disambiguation)

The literature used here matches the requested target:

  • hHSS1 (human hematopoietic signal peptide-containing secreted 1) has been explicitly identified as EMC10 (ER membrane protein complex subunit 10) in a glioma-focused study, and C19orf63 appears as a keyword/synonym in that same paper, aligning with UniProt synonyms provided in the prompt. Publication date: 2014-12; URL: http://www.biomedcentral.com/1471-2407/14/920 (junesgill2014humanhematopoieticsignal pages 1-2)
  • High-resolution human EMC structural studies explicitly include EMC10 as one of the subunits modeled within the nine-subunit human EMC. Publication date: 2020-07; URL: https://doi.org/10.1126/science.abb5008 (pleiner2020structuralbasisfor pages 1-3)

No conflicting gene symbol usage was encountered in retrieved materials; all “EMC10” references examined correspond to the human ER membrane protein complex subunit 10 context. (junesgill2014humanhematopoieticsignal pages 1-2, pleiner2020structuralbasisfor pages 1-3)

2) Key concepts and definitions (current understanding)

The ER membrane protein complex (EMC)

The EMC is an ER-resident multi-subunit assembly that acts as an insertase and chaperone/holdase supporting membrane-protein biogenesis, particularly for low-hydrophobicity TMDs (e.g., many tail-anchored proteins and certain multipass proteins). (pleiner2023aselectivityfilter pages 1-2, li2024structuralinsightsinto pages 1-3)

A key mechanistic concept is the hydrophilic vestibule within the membrane (primarily formed by core transmembrane subunits such as EMC3/EMC6, and supported by other subunits) that lowers the energetic barrier for integrating challenging TMDs and translocating short polar segments. (pleiner2020structuralbasisfor pages 1-3, pleiner2023aselectivityfilter pages 1-2)

Where EMC10 fits

EMC10 is best understood as an auxiliary/scaffold-like subunit in the lumenal module of the EMC, rather than as the catalytic insertase core.

  • In a 3.4 Å cryo-EM structure of the human nine-subunit EMC in lipid nanodiscs, EMC10 is positioned in the lumenal, L-shaped region together with EMC1/EMC4/EMC7; the lumenal domain of EMC10 was built into the density map. Publication date: 2020-07; URL: https://doi.org/10.1126/science.abb5008 (pleiner2020structuralbasisfor pages 1-3)
  • Weak/flexible density was observed for putative transmembrane helices associated with EMC4/EMC7/EMC10, consistent with a relatively dynamic membrane-proximal architecture for EMC10. (pleiner2020structuralbasisfor pages 1-3)

Thus, for functional annotation, EMC10’s “primary function” is most defensibly described as participation in a membrane protein biogenesis/quality-control complex, not an enzyme reaction or substrate transporter in its own right. (pleiner2020structuralbasisfor pages 1-3, millervedam2020structuralandmechanistic pages 18-21)

3) Molecular function, subcellular localization, and topology

Subcellular localization

Structural evidence places EMC10 on the ER-lumenal side of the EMC (i.e., lumen-facing domain) with a membrane anchor.

  • In human EMC cryo-EM, EMC10 is part of the lumenal region adjacent to EMC1 and EMC7. (pleiner2020structuralbasisfor pages 1-3)
  • In a client-bound EMC structure (EMC–CaV complex), the lumenal domain comprising EMC1, EMC4, EMC7, and EMC10 undergoes a measurable conformational change during client engagement (movement/tilt of lumenal module). Publication date: 2023-07; URL: https://doi.org/10.1038/s41586-023-06175-5 (chen2023emcchaperone–cavstructure pages 8-9)

Membrane topology

An improved cryo-EM model explicitly depicts the single-pass topology of EMC10:

  • A cropped panel from Pleiner et al. (J Cell Biol, 2023-05) Figure 3A labels the single TMDs of EMC7 and EMC10 in the human EMC model, providing direct visual support for EMC10’s single-pass membrane topology in the complex. Publication date: 2023-05; URL: https://doi.org/10.1083/jcb.202212007 (pleiner2023aselectivityfilter media 41b09963)

Molecular function (as distinct from complex function)

No specific enzymatic or transporter activity is attributed to EMC10 itself in the cited primary structural studies. Instead, EMC10 is best classified as a non-catalytic structural subunit within a multi-subunit insertase/chaperone system.

  • The 2020 Science structure emphasizes EMC’s insertase mechanism via an enclosed hydrophilic vestibule within the membrane formed mainly by core subunits (not EMC10), while EMC10 contributes to the lumenal module architecture. (pleiner2020structuralbasisfor pages 1-3)
  • Additional structural analysis describes EMC10 as part of the lumenal scaffold-like region together with EMC1/EMC7, consistent with an architectural/support role. (millervedam2020structuralandmechanistic pages 18-21)

4) Recent developments and latest research (prioritizing 2023–2024)

4.1. 2023: EMC selectivity filter and topology enforcement

A major 2023 mechanistic advance was identification of a selectivity filter at the EMC that helps prevent misinsertion and enforces correct topology.

  • Pleiner et al. (J Cell Biol, 2023-05) used improved structural modeling plus mutagenesis/crosslinking to map TA-protein engagement and showed that positively charged residues at the hydrophilic vestibule entrance provide charge-based discrimination, limiting misinsertion of mitochondrial TA proteins and enforcing the “positive-inside” rule for some multipass substrates. URL: https://doi.org/10.1083/jcb.202212007 (pleiner2023aselectivityfilter pages 1-2, pleiner2023aselectivityfilter pages 10-11)

Although this paper is not EMC10-specific mechanistically, it is directly relevant to EMC10 annotation because it employs an improved EMC structural model that includes EMC10 topology and emphasizes that certain subunits (including EMC10) have dynamic TMDs providing a protected environment during insertion decisions. (pleiner2023aselectivityfilter pages 10-11, pleiner2023aselectivityfilter media 41b09963)

4.2. 2023: First structural view of an EMC–client complex (holdase/chaperone mode)

A landmark 2023 Nature study solved cryo-EM structures of EMC bound to a voltage-gated calcium channel assembly intermediate, providing direct evidence for EMC’s holdase/chaperone roles.

  • Chen et al. (Nature, 2023-07) present EMC–client cryo-EM structures and report that binding causes a conformational change in the EMC lumenal domain (EMC1/EMC4/EMC7/EMC10), supporting a model where distinct EMC conformations may correspond to client-loaded states. URL: https://doi.org/10.1038/s41586-023-06175-5 (chen2023emcchaperone–cavstructure pages 1-3, chen2023emcchaperone–cavstructure pages 8-9)

This strengthens the interpretation that EMC10, as part of the lumenal module, may contribute to conformational coupling and/or stabilization during client engagement, even if it is not the catalytic insertase element. (chen2023emcchaperone–cavstructure pages 8-9, millervedam2020structuralandmechanistic pages 18-21)

4.3. 2024: EMC structural states at mitochondria–ER contact sites (VDAC-bound)

A 2024 paper provided additional EMC structural states relevant to multifunctionality.

  • Li et al. (Aging (Albany NY), 2024-03-15) report apo- and VDAC-bound human EMC cryo-EM structures and describe a “gating plug” inside the EMC hydrophilic vestibule. They propose that in the VDAC1-bound state, EMC is unlikely to act as an insertase, suggesting state-dependent functional switching. URL: https://doi.org/10.18632/aging.205660 (li2024structuralinsightsinto pages 1-3)

While not focused on EMC10 specifically, this contributes to current expert interpretation: EMC10 should be annotated within a complex that is conformationally and functionally versatile, with EMC10 embedded in the lumenal module that can move during client interactions. (li2024structuralinsightsinto pages 1-3, chen2023emcchaperone–cavstructure pages 8-9)

5) Secreted/soluble EMC10 forms (“moonlighting” biology) and signaling

A recurring theme in EMC10 literature is the existence of secreted or soluble EMC10-related products, raising an annotation challenge: separating the EMC-bound subunit role from a secreted signaling factor.

5.1. Secreted splice variant (HSS1/EMC10-2)

A review synthesis reports that EMC10 exists both as a full-length, membrane-bound EMC subunit and as a splice variant EMC10-2 (HSS1) lacking a discernible TMD and being secreted. (volkmar2020squaringtheemc pages 10-11)

In glioma-derived cell models:

  • Junes-Gill et al. (BMC Cancer, 2014-12) report that U87 cells overexpressing hHSS1 showed reduced G0/G1 and increased S and G2/M phases (P < 0.05), reduced migration (P < 0.001) and invasion (P < 0.01), and that purified hHSS1 inhibited HUVEC tube formation. They also report TCGA correlations (e.g., BRCA2 r = −0.224, P < 0.0005). URL: http://www.biomedcentral.com/1471-2407/14/920 (junesgill2014humanhematopoieticsignal pages 1-2)

These results support biological activity of a secreted EMC10-related factor in vitro, but they do not establish the mechanism of action or receptor identity, and they likely relate specifically to the secreted HSS1/EMC10-2 product rather than the EMC-incorporated subunit. (volkmar2020squaringtheemc pages 10-11, junesgill2014humanhematopoieticsignal pages 1-2)

5.3. Myocardial infarction repair: Emc10 as a secreted angiogenic growth factor

A key in vivo translational study reports secreted Emc10 after MI.

  • Reboll et al. (Circulation, 2017-11-07) identify Emc10 as a bone marrow-derived angiogenic growth factor in mice after myocardial infarction. They report that circulating plasma Emc10 increases after MI, that Emc10 is secreted into supernatants of isolated inflammatory cells, and that 85±2% of Emc10+ cells in infarct region coexpress macrophage marker F4/80. Recombinant Emc10 treatment (osmotic minipumps) enhanced border-zone capillarization and improved remodeling outcomes in a heart-failure-prone mouse strain. URL: https://doi.org/10.1161/CIRCULATIONAHA.117.029980 (reboll2017emc10(endoplasmicreticulum pages 1-2, reboll2017emc10(endoplasmicreticulum pages 9-10)

This study provides one of the strongest “real-world implementation” examples: recombinant protein delivery as a therapy concept in an animal model. (reboll2017emc10(endoplasmicreticulum pages 1-2, reboll2017emc10(endoplasmicreticulum pages 9-10)

6) Disease associations and human genetics

Direct, EMC10-specific disease mechanisms are still emerging, but authoritative association resources implicate EMC10 in neurodevelopmental phenotypes.

  • Open Targets lists EMC10 associations with Neurodevelopmental disorder and a more specific phenotype label “neurodevelopmental disorder with dysmorphic facies and variable seizures,” along with broader “genetic disorder” and “hypertension” associations. (OpenTargets Search: -EMC10)

These associations should be interpreted as gene–disease evidence links rather than definitive mechanistic proof; nonetheless, they prioritize EMC10 for deeper human genetics follow-up (variant interpretation, functional assays). (OpenTargets Search: -EMC10)

7) Current applications and real-world implementations

  1. Structural biology and mechanistic modeling of membrane-protein biogenesis: EMC10 is routinely treated as part of the EMC lumenal module in cryo-EM and mechanistic studies, enabling modeling of insertase/chaperone cycles and topology enforcement. (pleiner2020structuralbasisfor pages 1-3, pleiner2023aselectivityfilter pages 1-2, chen2023emcchaperone–cavstructure pages 8-9)
  2. Therapeutic concept (preclinical): recombinant Emc10 delivery improved post-MI angiogenesis/remodeling in mice, representing a direct application of EMC10-related biology. (reboll2017emc10(endoplasmicreticulum pages 1-2, reboll2017emc10(endoplasmicreticulum pages 9-10)
  3. Cancer biology exploratory applications: hHSS1/EMC10-2 was proposed as a potential therapeutic factor for malignant glioblastoma based on in vitro activity and transcriptional/network effects, but remains preclinical and mechanistically unresolved. (junesgill2014humanhematopoieticsignal pages 1-2)

8) Expert analysis and interpretive synthesis (authoritative sources)

Consensus interpretation from structural and mechanistic studies: EMC10 is best annotated primarily as an ER membrane complex subunit contributing to EMC architecture and conformational states during client handling, rather than directly binding substrates as the catalytic insertase element.

  • The human EMC structure positions EMC10 in the lumenal module with a flexible TMD, consistent with an accessory role. (pleiner2020structuralbasisfor pages 1-3)
  • The 2023 selectivity-filter study integrates improved structural modeling with functional discrimination at the vestibule entrance and explicitly depicts EMC10 as a single-pass component of a dynamic transmembrane region (supporting a role in creating a protected insertion environment rather than dictating substrate selectivity itself). (pleiner2023aselectivityfilter pages 10-11, pleiner2023aselectivityfilter media 41b09963)
  • The 2023 client-bound structure shows movement of the lumenal module (including EMC10), indicating that the region EMC10 occupies participates in client-induced conformational changes and may help communicate “client-loaded” states. (chen2023emcchaperone–cavstructure pages 8-9)

Important caveat for annotation: A substantial portion of the EMC10 literature concerns secreted EMC10-related factors (HSS1/EMC10-2). Functional claims about angiogenesis or tumor suppression likely refer to soluble products and should not be conflated with the EMC-incorporated EMC10 subunit unless isoform usage is experimentally clarified. (volkmar2020squaringtheemc pages 10-11, junesgill2014humanhematopoieticsignal pages 1-2, reboll2017emc10(endoplasmicreticulum pages 1-2)

9) Summary table of key findings

Aspect Key findings Evidence type Key sources (date; URL) Citeable context IDs
Identity / synonyms • Verified target is human EMC10 = ER membrane protein complex subunit 10 • UniProt Q5UCC4 matches literature aliases HSM1/HSS1/C19orf63 • Literature distinguishes membrane-bound EMC10 from secreted HSS1/EMC10-2 splice product Literature cross-mapping; review synthesis; structural papers Pleiner et al., Science (2020 Jul); https://doi.org/10.1126/science.abb5008 • Volkmar & Christianson, J Cell Sci (2020 Apr); https://doi.org/10.1242/jcs.243519 • Junes-Gill et al., BMC Cancer (2014 Dec); http://www.biomedcentral.com/1471-2407/14/920 (pleiner2020structuralbasisfor pages 1-3, volkmar2020squaringtheemc pages 10-11, junesgill2014humanhematopoieticsignal pages 1-2)
Localization / topology • EMC10 is an ER-associated EMC subunit positioned on the ER-lumenal face • Human cryo-EM places EMC10 in the lumenal L-shaped region with EMC1/EMC7 • EMC10 has a single, flexible TMD; improved cryo-EM explicitly visualized/labeled EMC10 TMD topology Cryo-EM structure; image/figure inspection Pleiner et al., Science (2020 Jul); https://doi.org/10.1126/science.abb5008 • Pleiner et al., J Cell Biol (2023 May); https://doi.org/10.1083/jcb.202212007 (pleiner2020structuralbasisfor pages 1-3, pleiner2023aselectivityfilter media 41b09963)
Role in EMC complex • EMC10 is a non-catalytic accessory/scaffold-like lumenal subunit, not the insertase core • Contacts/positions near EMC1 and EMC7 on the lumenal side • EMC7 loss can lead to loss of EMC10 from assembled complex, supporting an auxiliary stabilizing role Cryo-EM; mutational/assembly analysis; review synthesis Miller-Vedam et al., eLife (2020 Sep); https://doi.org/10.1101/2020.09.02.280008 • Pleiner et al., Science (2020 Jul); https://doi.org/10.1126/science.abb5008 (millervedam2020structuralandmechanistic pages 18-21, pleiner2020structuralbasisfor pages 1-3)
Primary molecular function • No enzyme or transporter activity has been established for EMC10 itself • Best-supported primary function is as a structural/auxiliary EMC subunit supporting membrane protein biogenesis • Functional effect is indirect, through the EMC machinery that inserts or stabilizes select membrane-protein TMDs Structural inference; complex-level functional studies Pleiner et al., Science (2020 Jul); https://doi.org/10.1126/science.abb5008 • Bai & Li, FEBS J (2022 Mar); https://doi.org/10.1111/febs.15786 • Li et al., Aging (Albany NY) (2024 Mar 15); https://doi.org/10.18632/aging.205660 (pleiner2020structuralbasisfor pages 1-3, li2024structuralinsightsinto pages 1-3)
Insertase / chaperone mechanism context • EMC core insertase activity resides mainly in EMC3/EMC6 hydrophilic vestibule, with EMC10 peripheral to this core • 2023 work defined a selectivity filter at the EMC that rejects misinserted positively charged TA substrates and enforces topology • 2023 client-bound structure supports EMC holdase/chaperone function for CaV channel assembly; lumenal module including EMC10 shifts during client engagement Cryo-EM; mutagenesis; client-bound structural biology Pleiner et al., J Cell Biol (2023 May); https://doi.org/10.1083/jcb.202212007 • Chen et al., Nature (2023 Jul); https://doi.org/10.1038/s41586-023-06175-5 • Li et al., Aging (Albany NY) (2024 Mar 15); https://doi.org/10.18632/aging.205660 (pleiner2023aselectivityfilter pages 1-2, pleiner2023aselectivityfilter pages 10-11, chen2023emcchaperone–cavstructure pages 1-3, chen2023emcchaperone–cavstructure pages 8-9, li2024structuralinsightsinto pages 1-3)
Secreted isoform / soluble form • Alternative splice variant EMC10-2 / HSS1 lacks a discernible TMD and is secreted • Secreted EMC10/HSS1 showed reported anti-glioma/anti-angiogenic effects in glioma assays • A separate cardiovascular study identified secreted EMC10/Emc10 from bone marrow-derived monocytes/macrophages as a pro-angiogenic growth factor after MI, indicating context/isoform-dependent biology Cell culture functional assays; recombinant protein; mouse MI models Junes-Gill et al., BMC Cancer (2014 Dec); http://www.biomedcentral.com/1471-2407/14/920 • Reboll et al., Circulation (2017 Nov); https://doi.org/10.1161/CIRCULATIONAHA.117.029980 • Volkmar & Christianson, J Cell Sci (2020 Apr); https://doi.org/10.1242/jcs.243519 (junesgill2014humanhematopoieticsignal pages 1-2, reboll2017emc10(endoplasmicreticulum pages 1-2, reboll2017emc10(endoplasmicreticulum pages 9-10, volkmar2020squaringtheemc pages 10-11)
Signaling linked to soluble EMC10 • In endothelial/cardiac repair studies, Emc10 signaled via small GTPases, PAK, p38 MAPK, and MK2 to promote actin polymerization and migration • In glioma-related studies, overexpression altered cell-cycle/tumorigenic transcriptional programs and reduced migration/invasion • These signaling findings concern the soluble/secreted form, not necessarily the EMC-bound ER subunit Recombinant protein; cell migration assays; transcriptomics; mouse infarct explants Reboll et al., Circulation (2017 Nov); https://doi.org/10.1161/CIRCULATIONAHA.117.029980 • Junes-Gill et al., BMC Cancer (2014 Dec); http://www.biomedcentral.com/1471-2407/14/920 (reboll2017emc10(endoplasmicreticulum pages 1-2, reboll2017emc10(endoplasmicreticulum pages 9-10, junesgill2014humanhematopoieticsignal pages 1-2)
Disease / phenotype associations • Open Targets lists associations with neurodevelopmental disorder, including neurodevelopmental disorder with dysmorphic facies and variable seizures, plus broader genetic disorder/hypertension links • EMC as a complex is implicated in neurological disease, diabetes, cancer, and membrane-protein proteostasis defects • Evidence is stronger at the gene-disease association level than for a fully resolved EMC10-specific molecular mechanism in these disorders Database association; literature synthesis Open Targets association context (retrieved current database evidence) • Li et al., Aging (Albany NY) (2024 Mar 15); https://doi.org/10.18632/aging.205660 (OpenTargets Search: -EMC10, li2024structuralinsightsinto pages 1-3)
Quantitative phenotype highlights • Glioma study: hHSS1 overexpression changed cell-cycle distribution (G0/G1 down, S and G2/M up; P<0.05) and reduced migration/invasion (P<0.001 to P<0.01) • TCGA correlations reported for BRCA2 r = -0.224 (P<0.0005), ADAMTS1 r = -0.132 (P<0.01), endostatin r = 0.141 (P<0.005) • MI study: 85±2% of Emc10+ cells in infarct region coexpressed F4/80 macrophage marker Cell biology assays; TCGA correlation; mouse histology Junes-Gill et al., BMC Cancer (2014 Dec); http://www.biomedcentral.com/1471-2407/14/920 • Reboll et al., Circulation (2017 Nov); https://doi.org/10.1161/CIRCULATIONAHA.117.029980 (junesgill2014humanhematopoieticsignal pages 1-2, reboll2017emc10(endoplasmicreticulum pages 9-10)
Applications / translation • EMC biology is relevant to membrane-protein biogenesis, affecting ion channels, receptors, transporters, and viral proteins—important because many drug targets are membrane proteins • Secreted Emc10 showed proof-of-concept therapeutic benefit in mouse post-MI repair when delivered by osmotic minipump • EMC machinery is being considered in virus-host biology and protein-quality-control research, but there is no EMC10-targeted approved therapy Structural biology; translational mouse model; review Pleiner et al., Science (2020 Jul); https://doi.org/10.1126/science.abb5008 • Reboll et al., Circulation (2017 Nov); https://doi.org/10.1161/CIRCULATIONAHA.117.029980 • Woo et al., J Cell Sci (2023 Jul); https://doi.org/10.1242/jcs.261121 (pleiner2020structuralbasisfor pages 1-3, reboll2017emc10(endoplasmicreticulum pages 1-2, reboll2017emc10(endoplasmicreticulum pages 9-10)

Table: This table summarizes the best-supported functional annotation for human EMC10/Q5UCC4, separating its likely primary role as an ER-lumenal accessory EMC subunit from reported biology of secreted EMC10/HSS1 isoforms. It also highlights recent 2023–2024 structural advances, disease links, and quantitative findings useful for downstream annotation.

10) Conclusion

Human EMC10 (UniProt Q5UCC4) is most strongly supported as a single-pass, ER-associated subunit of the EMC, residing in the lumenal module and contributing structurally to a versatile insertase/holdase machine that controls insertion and topology of select membrane proteins. The most important recent advances (2023–2024) strengthen a model in which EMC10 participates in client-induced conformational changes and a dynamic transmembrane environment, while core substrate discrimination is mediated by conserved charge features within the EMC’s hydrophilic vestibule. In parallel, secreted EMC10-related isoforms (e.g., HSS1/EMC10-2) have been implicated in signaling and tissue repair, including proof-of-concept recombinant protein therapy in a mouse MI model, but the relationship between these soluble forms and the canonical EMC subunit role remains an active area for clarification. (pleiner2023aselectivityfilter media 41b09963, chen2023emcchaperone–cavstructure pages 8-9, li2024structuralinsightsinto pages 1-3, reboll2017emc10(endoplasmicreticulum pages 1-2)

References

  1. (pleiner2020structuralbasisfor pages 1-3): Tino Pleiner, Giovani Pinton Tomaleri, Kurt Januszyk, Alison J. Inglis, Masami Hazu, and Rebecca M. Voorhees. Structural basis for membrane insertion by the human er membrane protein complex. Jul 2020. URL: https://doi.org/10.1126/science.abb5008, doi:10.1126/science.abb5008. This article has 192 citations and is from a highest quality peer-reviewed journal.

  2. (volkmar2020squaringtheemc pages 10-11): Norbert Volkmar and John C. Christianson. Squaring the emc – how promoting membrane protein biogenesis impacts cellular functions and organismal homeostasis. Journal of Cell Science, Apr 2020. URL: https://doi.org/10.1242/jcs.243519, doi:10.1242/jcs.243519. This article has 59 citations and is from a domain leading peer-reviewed journal.

  3. (pleiner2023aselectivityfilter pages 1-2): Tino Pleiner, Masami Hazu, Giovani Pinton Tomaleri, Vy N. Nguyen, Kurt Januszyk, and Rebecca M. Voorhees. A selectivity filter in the er membrane protein complex limits protein misinsertion at the er. The Journal of Cell Biology, May 2023. URL: https://doi.org/10.1083/jcb.202212007, doi:10.1083/jcb.202212007. This article has 28 citations.

  4. (chen2023emcchaperone–cavstructure pages 1-3): Zhou Chen, Abhisek Mondal, Fayal Abderemane-Ali, Seil Jang, Sangeeta Niranjan, José L. Montaño, Balyn W. Zaro, and Daniel L. Minor. Emc chaperone–cav structure reveals an ion channel assembly intermediate. Nature, 619:410-419, May 2023. URL: https://doi.org/10.1038/s41586-023-06175-5, doi:10.1038/s41586-023-06175-5. This article has 77 citations and is from a highest quality peer-reviewed journal.

  5. (li2024structuralinsightsinto pages 1-3): Mingyue Li, Chunli Zhang, Yuntao Xu, Shaobai Li, Chenhui Huang, Jian Wu, and Ming Lei. Structural insights into human emc and its interaction with vdac. Aging (Albany NY), 16:5501-5525, Mar 2024. URL: https://doi.org/10.18632/aging.205660, doi:10.18632/aging.205660. This article has 6 citations.

  6. (junesgill2014humanhematopoieticsignal pages 1-2): Katiana S Junes-Gill, Chris E Lawrence, Christopher J Wheeler, Ryan Cordner, Tristan G Gill, Vernon Mar, Liron Shiri, and Lena A Basile. Human hematopoietic signal peptide-containing secreted 1 (hhss1) modulates genes and pathways in glioma: implications for the regulation of tumorigenicity and angiogenesis. BMC Cancer, Dec 2014. URL: https://doi.org/10.1186/1471-2407-14-920, doi:10.1186/1471-2407-14-920. This article has 46 citations and is from a peer-reviewed journal.

  7. (millervedam2020structuralandmechanistic pages 18-21): Lakshmi E. Miller-Vedam, Bastian Bräuning, Katerina D. Popova, Nicole T. Schirle Oakdale, Jessica L. Bonnar, Jesuraj Rajan Prabu, Elizabeth A. Boydston, Natalia Sevillano, Matthew J. Shurtleff, Robert M. Stroud, Charles S. Craik, Brenda A. Schulman, Adam Frost, and Jonathan S. Weissman. Structural and mechanistic basis of the emc-dependent biogenesis of distinct transmembrane clients. eLife, Sep 2020. URL: https://doi.org/10.1101/2020.09.02.280008, doi:10.1101/2020.09.02.280008. This article has 102 citations and is from a domain leading peer-reviewed journal.

  8. (chen2023emcchaperone–cavstructure pages 8-9): Zhou Chen, Abhisek Mondal, Fayal Abderemane-Ali, Seil Jang, Sangeeta Niranjan, José L. Montaño, Balyn W. Zaro, and Daniel L. Minor. Emc chaperone–cav structure reveals an ion channel assembly intermediate. Nature, 619:410-419, May 2023. URL: https://doi.org/10.1038/s41586-023-06175-5, doi:10.1038/s41586-023-06175-5. This article has 77 citations and is from a highest quality peer-reviewed journal.

  9. (pleiner2023aselectivityfilter media 41b09963): Tino Pleiner, Masami Hazu, Giovani Pinton Tomaleri, Vy N. Nguyen, Kurt Januszyk, and Rebecca M. Voorhees. A selectivity filter in the er membrane protein complex limits protein misinsertion at the er. The Journal of Cell Biology, May 2023. URL: https://doi.org/10.1083/jcb.202212007, doi:10.1083/jcb.202212007. This article has 28 citations.

  10. (pleiner2023aselectivityfilter pages 10-11): Tino Pleiner, Masami Hazu, Giovani Pinton Tomaleri, Vy N. Nguyen, Kurt Januszyk, and Rebecca M. Voorhees. A selectivity filter in the er membrane protein complex limits protein misinsertion at the er. The Journal of Cell Biology, May 2023. URL: https://doi.org/10.1083/jcb.202212007, doi:10.1083/jcb.202212007. This article has 28 citations.

  11. (reboll2017emc10(endoplasmicreticulum pages 1-2): Marc R. Reboll, Mortimer Korf-Klingebiel, Stefanie Klede, Felix Polten, Eva Brinkmann, Ines Reimann, Hans-Joachim Schönfeld, Maria Bobadilla, Jan Faix, George Kensah, Ina Gruh, Michael Klintschar, Matthias Gaestel, Hans W. Niessen, Andreas Pich, Johann Bauersachs, Joseph A. Gogos, Yong Wang, and Kai C. Wollert. Emc10 (endoplasmic reticulum membrane protein complex subunit 10) is a bone marrow–derived angiogenic growth factor promoting tissue repair after myocardial infarction. Circulation, 136:1809–1823, Nov 2017. URL: https://doi.org/10.1161/circulationaha.117.029980, doi:10.1161/circulationaha.117.029980. This article has 55 citations and is from a highest quality peer-reviewed journal.

  12. (reboll2017emc10(endoplasmicreticulum pages 9-10): Marc R. Reboll, Mortimer Korf-Klingebiel, Stefanie Klede, Felix Polten, Eva Brinkmann, Ines Reimann, Hans-Joachim Schönfeld, Maria Bobadilla, Jan Faix, George Kensah, Ina Gruh, Michael Klintschar, Matthias Gaestel, Hans W. Niessen, Andreas Pich, Johann Bauersachs, Joseph A. Gogos, Yong Wang, and Kai C. Wollert. Emc10 (endoplasmic reticulum membrane protein complex subunit 10) is a bone marrow–derived angiogenic growth factor promoting tissue repair after myocardial infarction. Circulation, 136:1809–1823, Nov 2017. URL: https://doi.org/10.1161/circulationaha.117.029980, doi:10.1161/circulationaha.117.029980. This article has 55 citations and is from a highest quality peer-reviewed journal.

  13. (OpenTargets Search: -EMC10): Open Targets Query (-EMC10, 5 results). Buniello, A. et al. (2025). Open Targets Platform: facilitating therapeutic hypotheses building in drug discovery. Nucleic Acids Research.

Artifacts

Citations

  1. junesgill2014humanhematopoieticsignal pages 1-2
  2. pleiner2020structuralbasisfor pages 1-3
  3. millervedam2020structuralandmechanistic pages 18-21
  4. li2024structuralinsightsinto pages 1-3
  5. volkmar2020squaringtheemc pages 10-11
  6. pleiner2023aselectivityfilter pages 1-2
  7. pleiner2023aselectivityfilter pages 10-11
  8. http://www.biomedcentral.com/1471-2407/14/920
  9. https://doi.org/10.1126/science.abb5008
  10. https://doi.org/10.1038/s41586-023-06175-5
  11. https://doi.org/10.1083/jcb.202212007
  12. https://doi.org/10.18632/aging.205660
  13. https://doi.org/10.1161/CIRCULATIONAHA.117.029980
  14. https://doi.org/10.1242/jcs.243519
  15. https://doi.org/10.1101/2020.09.02.280008
  16. https://doi.org/10.1111/febs.15786
  17. https://doi.org/10.1242/jcs.261121
  18. https://doi.org/10.1126/science.abb5008,
  19. https://doi.org/10.1242/jcs.243519,
  20. https://doi.org/10.1083/jcb.202212007,
  21. https://doi.org/10.1038/s41586-023-06175-5,
  22. https://doi.org/10.18632/aging.205660,
  23. https://doi.org/10.1186/1471-2407-14-920,
  24. https://doi.org/10.1101/2020.09.02.280008,
  25. https://doi.org/10.1161/circulationaha.117.029980,

📚 Additional Documentation

Notes

(EMC10-notes.md)

EMC10 (Q5UCC4) review notes

Identity / domain architecture

  • Human EMC10 = "ER membrane protein complex subunit 10" (C19orf63, INM02). 262 aa precursor; N-terminal signal peptide (1..25), large lumenal domain (26..221), single TM helix (222..242), short cytoplasmic tail (243..262). Single-pass type I ER membrane protein, N-glycosylated at Asn-182 [file:human/EMC10/EMC10-uniprot.txt "Single-pass type I membrane protein"], [file: "N-linked (GlcNAc...) asparagine"].
  • It is the LUMENAL/peripheral subunit of the EMC; structural cryo-EM studies (PMID:32439656, PMID:32459176) place EMC10's bulk in the ER lumen. It is NOT a catalytic insertase subunit (the membrane insertase core is EMC3/EMC6).
  • Belongs to the EMC10 family; Pfam PF21203, TCDB 3.A.27.1.1 (EMC family) [file: "the endoplasmic reticulum membrane protein insertion complex (emc) family"].

Core function = EMC complex membership + ER membrane

  • EMC is a transmembrane-domain insertase/chaperone enabling energy-independent insertion of newly synthesized membrane proteins into the ER membrane; inserts tail-anchored (TA) proteins post-translationally and multipass membrane proteins co-translationally, and sets N-exo topology of multipass proteins (e.g. GPCRs) [file: "enables the energy-independent insertion into endoplasmic reticulum membranes of newly synthesized membrane proteins"].
  • EMC10 is a bona fide EMC subunit: identified in the EMC by AP-MS in the ERAD-network study PMID:22119785, and present in the cryo-EM EMC structure PMID:32439656. UniProt SUBUNIT: "Component of the ER membrane protein complex (EMC)." [file: "Component of the ER membrane protein complex (EMC)."]
  • The insertase activity is a property of the holo-complex; EMC10 "contributes_to" membrane insertase activity (GO:0032977) in IMP screens [PMID:29809151, PMID:30415835]. For a non-catalytic lumenal subunit, the core MF is complex membership, not standalone insertase catalysis. The contributes_to qualifier is appropriate and is kept as non-core.

Secreted form / HSS1 / angiogenesis (peripheral, isoform 2)

  • Isoform 2 (Q5UCC4-2) = "Hematopoietic Signal peptide-containing Secreted 1" (HSS1); isoform 1 = HSM1 (membrane). Junes-Gill et al. described HSS1/HSM1 from hematopoietic stem cells; HSS1 is secreted and suppresses glioma growth PMID:20680400.
  • INM02 (= EMC10) is detectable in human serum and glucose-regulated in islets PMID:19570817.
  • Reboll et al.: secreted EMC10 is a bone marrow-derived angiogenic growth factor; stimulates endothelial cell migration/outgrowth via p38 MAPK/MK2/PAK after MI PMID:28931551, [file: "Stimulates cardiac endothelial cell migration and outgrowth via the activation of p38 MAPK, PAK and MAPK2 signaling pathways"].
  • These secreted/angiogenesis roles are real (EXP/IDA/IMP supported) but are peripheral to EMC's core ER membrane-insertion function and pertain largely to the secreted isoform → KEEP_AS_NON_CORE.

Disease

  • Biallelic loss-of-function variants cause NEDDFAS (neurodevelopmental disorder with dysmorphic facies and variable seizures; MIM:619264) [PMID:32869858, PMID:33531666]. Consistent with EMC being broadly required for membrane proteostasis.

Annotation review decisions

  • EMC complex (GO:0072546) IBA/IPI/IDA, ER membrane (GO:0005789) IDA/IEA/NAS → ACCEPT, CORE.
  • membrane insertase activity (GO:0032977) contributes_to, IMP → KEEP_AS_NON_CORE (complex-level catalysis; EMC10 lumenal subunit contributes but is not catalytic).
  • protein insertion into ER membrane by stop-transfer (GO:0045050) and tail-anchored insertion (GO:0071816), IDA/IMP → KEEP_AS_NON_CORE (correct EMC processes but EMC10 is a structural subunit; complex-level BP).
  • membrane (GO:0016020) IDA → ACCEPT (correct but generic vs ER membrane).
  • extracellular region (GO:0005576) EXP×3 + IEA → KEEP_AS_NON_CORE (real secreted isoform 2 / serum, peripheral to EMC).
  • angiogenesis terms GO:0045766, GO:0010595, GO:0001938 → KEEP_AS_NON_CORE (real but secreted-form moonlighting, peripheral).
  • No clearly wrong IEA to REMOVE; no unverifiable experimental annotations requiring UNDECIDED (all cited PMIDs cached, organism human).

Cached publication status

  • full_text_available: 29242231 true, 22119785 true, 20680400 true, 30415835 (check), 29809151 (check); 32439656 false, 28931551 false, 19570817 false (abstract only). For abstract-only papers, supporting_text drawn from UniProt file or abstract.

Falcon deep-research findings (incorporated 2026-06)

  • 2023 EMC-client structure: cryo-EM of the EMC bound to a CaV1.2 assembly intermediate defines EMC transmembrane (TM) and cytoplasmic (Cyto) client-docking sites and shows the EMC acts as a channel "holdase"; the EMC lumenal module (EMC1/EMC4/EMC7/EMC10) participates in client-induced conformational change. PMID:37196677. Supports interpreting EMC10's lumenal position as part of a conformationally coupled client-engagement module (EMC-level, not EMC10-catalytic).
  • 2023 selectivity filter: positively charged residues at the entrance of the EMC hydrophilic vestibule form a charge-based selectivity filter rejecting mitochondrial TA proteins and enforcing the "positive-inside" rule. PMID:37199759. Uses an improved human EMC model that resolves EMC7/EMC10 single-pass TMD topology, reinforcing EMC10 as a non-catalytic single-TMD lumenal subunit.
  • 2024 EMC-VDAC structure: apo- and VDAC-bound human EMC cryo-EM identify a "gating plug" in 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. PMID:38517390. Indicates the EMC (and thus EMC10's complex) is conformationally/functionally versatile.
  • Consensus across these structural papers: EMC10 is best annotated within a conformationally versatile insertase/holdase whose catalytic core is EMC3/EMC6; EMC10 contributes to the dynamic lumenal module. This corroborates the existing KEEP_AS_NON_CORE handling of EMC10's insertase-related annotations. (References: PMID:37196677, PMID:37199759, PMID:38517390 added to review.)
  • Note: the Falcon report also cites Miller-Vedam et al. 2020 eLife (EMC7 loss can drop EMC10 from the assembled complex, supporting EMC10 as an auxiliary stabilizing subunit) and Volkmar & Christianson 2020 J Cell Sci (membrane-bound vs secreted HSS1/EMC10-2 forms). These pre-2022 sources reinforce existing review content; not added as new structured references.

Pn Notes

(EMC10-pn-notes.md)

EMC10 PN Consistency Notes

  • Generated: 2026-06-18
  • Project: PROTEOSTASIS
  • Scope: PN consistency rereview against local AIGR review and available deep-research artifacts
  • UniProt: Q5UCC4
  • AIGR review status: COMPLETE
  • Review batch: proteostasis-batch-2026-06-11
  • Batch change status: added

Source Files Checked

Deep Research Files

AIGR Review Snapshot

  • 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.
  • Existing/core annotation action counts: ACCEPT: 6; KEEP_AS_NON_CORE: 14

PN Consistency Summary

  • Consistency: Deep research, review YAML, and PN annotation agree on the EMC role: EMC10 is a single-pass type I lumenal/peripheral, non-catalytic EMC subunit. The review additionally documents the secreted isoform 2 (HSS1/INM02) as an extracellular angiogenic growth factor (PMID:28931551, 20680400, 19570817) and biallelic-LoF NEDD (NEDDFAS) disease — a substantial moonlighting biology entirely outside the PN node's scope. Not a contradiction, but the PN row captures only the membrane-EMC facet.
  • PN story / NEW pressure: PN asserts only EMC membership + import/insertion, already captured (GO:0072546 part_of; insertion/insertase terms KEEP_AS_NON_CORE). No NEW GO term needed for the PN claim. The secreted-form functions are already annotated (GO:0001938, GO:0010595, GO:0045766, GO:0005576) and correctly KEEP_AS_NON_CORE — they are not a PN/ER-proteostasis story.
  • Evidence alignment: Core EMC papers overlap (22119785, 29242231, 32439656, 30415835); review adds EMC10-specific secreted-isoform and disease PMIDs absent from the PN row.
  • Verdict: Consistent for the EMC facet; well-reviewed. Shared group→GO:0044743 mapping diverges from insertion semantics; note EMC10's secreted angiogenic moonlighting is correctly non-core and outside PN scope.

Full Consistency Review

  • UniProt: Q5UCC4 · batch: proteostasis-batch-2026-06-11 · review status: COMPLETE
  • PN placement: ER proteostasis|Protein transport|Transmembrane protein import|EMC complex component ; PN-node mapping: type → GO:0072546 (EMC complex); group → GO:0044743 (protein transmembrane import into intracellular organelle); class → GO:0015031 (protein transport); branch=no_mapping.
  • Consistency: Deep research, review YAML, and PN annotation agree on the EMC role: EMC10 is a single-pass type I lumenal/peripheral, non-catalytic EMC subunit. The review additionally documents the secreted isoform 2 (HSS1/INM02) as an extracellular angiogenic growth factor (PMID:28931551, 20680400, 19570817) and biallelic-LoF NEDD (NEDDFAS) disease — a substantial moonlighting biology entirely outside the PN node's scope. Not a contradiction, but the PN row captures only the membrane-EMC facet.
  • PN story / NEW pressure: PN asserts only EMC membership + import/insertion, already captured (GO:0072546 part_of; insertion/insertase terms KEEP_AS_NON_CORE). No NEW GO term needed for the PN claim. The secreted-form functions are already annotated (GO:0001938, GO:0010595, GO:0045766, GO:0005576) and correctly KEEP_AS_NON_CORE — they are not a PN/ER-proteostasis story.
  • Mapping strategy: EMC10 does not change the shared node mapping (EMC complex member → GO:0072546 stands). Same group-level concern as EMC7-9: GO:0044743 (lumenal import) mismatches EMC membrane-protein insertion; insertion terms are not subclasses of it. The secreted/angiogenic facet argues against treating this node as capturing all of EMC10's biology, but is out of PN scope.
  • Evidence alignment: Core EMC papers overlap (22119785, 29242231, 32439656, 30415835); review adds EMC10-specific secreted-isoform and disease PMIDs absent from the PN row.
  • Verdict: Consistent for the EMC facet; well-reviewed. Shared group→GO:0044743 mapping diverges from insertion semantics; note EMC10's secreted angiogenic moonlighting is correctly non-core and outside PN scope.

PN Dossier Context

  • review_batch: proteostasis-batch-2026-06-11
  • review_yaml: genes/human/EMC10/EMC10-ai-review.yaml
  • PN workbook rows: 1

PN row 1: ER proteostasis | Protein transport | Transmembrane protein import | EMC complex component

  • UniProt: Q5UCC4
  • In branches: ER
  • PN-node mapping records (path + ancestors):
    • [type] ER proteostasis|Protein transport|Transmembrane protein import|EMC complex component
      status=mapped scope=ok_for_propagation_to_go GO=[GO:0072546 EMC complex]
      rationale: This PN type denotes ER membrane protein complex components. The GO EMC complex cellular-component term is the direct target.
    • [group] ER proteostasis|Protein transport|Transmembrane protein import
      status=mapped scope=ok_for_propagation_to_go GO=[GO:0044743 protein transmembrane import into intracellular organelle]
      rationale: This PN group covers ER transmembrane-protein insertion/import systems such as EMC- and PAT-related pathways. The local GO cache does not expose an ER-specific matching term, so the broader intracellular-organelle transmembrane-import process is the best supported propagation target.
    • [class] ER proteostasis|Protein transport
      status=mapped scope=ok_for_propagation_to_go GO=[GO:0015031 protein transport]
      rationale: The PN ER Protein transport class groups ER-targeting and ER-insertion pathways. GO protein transport is the appropriate propagation target, while the source class remains ER-specific and broader than any single GO transport subtype.
    • [branch] ER proteostasis
      status=no_mapping scope= GO=[]
      rationale: Reviewed as a top-level PN branch. This is a systems/taxonomy umbrella, not a direct GO assertion; narrower child curations carry any propagating GO mappings.

Projected GO annotations (3)

  • GO:0015031 protein transport | scope=ok_for_propagation_to_go | goa_status=new_to_goa | from=ER proteostasis|Protein transport
  • GO:0044743 protein transmembrane import into intracellular organelle | scope=ok_for_propagation_to_go | goa_status=new_to_goa | from=ER proteostasis|Protein transport|Transmembrane protein import
  • GO:0072546 EMC complex | scope=ok_for_propagation_to_go | goa_status=already_in_goa_exact | from=ER proteostasis|Protein transport|Transmembrane protein import|EMC complex component

Note

This file is generated from the current PROTEOSTASIS phase-1 dossier and local gene-review artifacts. Edit the source review, PN mapping, or dossier rather than this generated note when correcting the underlying curation.

📄 View Raw YAML

 
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.