EMC7

UniProt ID: Q9NPA0
Organism: Homo sapiens
Review Status: COMPLETE
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Gene Description

EMC7 (ER membrane protein complex subunit 7) is a 242 aa single-pass type I ER membrane protein and a constitutive subunit of the ER membrane protein complex (EMC), a conserved transmembrane-domain insertase and membrane-protein chaperone of the endoplasmic reticulum. After cleavage of its N-terminal signal peptide, EMC7 presents a large lumenal beta-sandwich domain followed by a single transmembrane helix and a short, partly disordered cytoplasmic tail. EMC7 is a peripheral, non-catalytic architectural subunit; the catalytic insertase machinery (the membrane-embedded hydrophilic vestibule) is formed by EMC3 and EMC6. As part of the EMC, EMC7 contributes to the energy-independent insertion of newly synthesized membrane proteins into the ER membrane, with a preference for transmembrane domains that are weakly hydrophobic or contain destabilizing residues, including post-translational insertion of tail-anchored proteins and cotranslational insertion and topogenesis of multipass membrane proteins. EMC7 localizes to the ER membrane and is broadly expressed.

Existing Annotations Review

GO Term Evidence Action Reason
GO:0072546 EMC complex
IBA
GO_REF:0000033 		ACCEPT
Summary: Phylogenetic assignment of EMC complex membership, consistent with direct experimental and structural identification of EMC7 in the EMC. This is the core structural identity of EMC7.
Reason: EMC complex membership is the core cellular-component identity of EMC7; supported by IDA, cryo-EM, and the conserved EMC7 family.
Supporting Evidence:
file:human/EMC7/EMC7-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; the correct and core compartment for EMC7.
Reason: Correct core location; redundant with experimental EXP/IDA evidence.
Supporting Evidence:
file:human/EMC7/EMC7-uniprot.txt
SUBCELLULAR LOCATION: Endoplasmic reticulum membrane
GO:0030246 carbohydrate binding
IEA
GO_REF:0000002 		MARK AS OVER ANNOTATED
Summary: InterPro fold-homology assignment derived from the lumenal beta-sandwich resembling a starch-binding/carbohydrate-binding-like domain. There is no experimental evidence that EMC7 binds carbohydrate; the fold is structural and the assignment is an over-propagated electronic inference.
Reason: Fold-similarity-only IEA with no supporting evidence that EMC7 actually binds carbohydrate; the beta-sandwich is structural and serves complex architecture.
Supporting Evidence:
file:human/EMC7/EMC7-uniprot.txt
Starch-binding domain-like
GO:0005515 protein binding
IPI
PMID:28514442
Architecture of the human interactome defines protein commun... 		KEEP AS NON CORE
Summary: High-throughput interactome capture (with PDIA4). Bare protein binding is uninformative.
Reason: High-throughput interaction; bare protein binding is uninformative per guidelines.
Supporting Evidence:
file:human/EMC7/EMC7-uniprot.txt
P13667: PDIA4
GO:0005515 protein binding
IPI
PMID:28734904
Identifying novel members of the Wntless interactome through... 		KEEP AS NON CORE
Summary: Interaction with WLS (Wntless), itself an EMC client, identified in a Wntless-interactome screen. The interaction plausibly reflects EMC client engagement, but bare protein binding is uninformative.
Reason: Likely reflects client engagement, but the bare term is uninformative and not core.
Supporting Evidence:
file:human/EMC7/EMC7-uniprot.txt
Q5T9L3-1: WLS
GO:0005515 protein binding
IPI
PMID:31286866
Alternative splicing of the Wnt trafficking protein, Wntless... 		KEEP AS NON CORE
Summary: Interaction with WLS from a Wntless splicing/PPI study. WLS is an EMC client; bare protein binding is uninformative.
Reason: Likely client engagement; bare term uninformative, not core.
Supporting Evidence:
file:human/EMC7/EMC7-uniprot.txt
Q5T9L3-1: WLS
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 captures (CYSRT1, NOTCH2NLC, keratin-associated proteins, MEOX2); several are likely sticky Y2H hits. Bare protein binding is uninformative.
Reason: High-throughput binary interactions of uncertain biological relevance; bare term uninformative.
Supporting Evidence:
file:human/EMC7/EMC7-uniprot.txt
A8MQ03: CYSRT1
GO:0005515 protein binding
IPI
PMID:33961781
Dual proteome-scale networks reveal cell-specific remodeling... 		KEEP AS NON CORE
Summary: BioPlex affinity-MS interactome capture (with PDIA4). Bare protein binding is uninformative.
Reason: High-throughput interaction; bare term uninformative, not core.
Supporting Evidence:
file:human/EMC7/EMC7-uniprot.txt
P13667: PDIA4
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. Core compartment.
Reason: Correct core location; consistent with EXP/IDA evidence.
Supporting Evidence:
file:human/EMC7/EMC7-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 domains, including stop-transfer membrane-anchor sequences of multipass proteins; EMC7 participates as an EMC subunit. A genuine EMC-mediated process, though EMC7 is non-catalytic.
Reason: Correct EMC-mediated process EMC7 is involved in as a complex subunit; non-core relative to complex membership.
Supporting Evidence:
PMID:29242231
EMC is a 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; EMC7 participates as an EMC subunit. Genuine EMC-mediated process.
Reason: Correct EMC-mediated process EMC7 participates in via membership.
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 EMC7.
Reason: Structurally demonstrated core EMC membership.
Supporting Evidence:
file:human/EMC7/EMC7-uniprot.txt
Component of the ER membrane protein complex (EMC).
GO:0005789 endoplasmic reticulum membrane
EXP
PMID:22119785
Defining human ERAD networks through an integrative mapping ... 		ACCEPT
Summary: Experimental ER membrane localization from the EMC-discovery ERAD-network study. Core compartment.
Reason: Experimentally supported core location.
Supporting Evidence:
file:human/EMC7/EMC7-uniprot.txt
SUBCELLULAR LOCATION: Endoplasmic reticulum membrane
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; EMC7 contributes_to the complex insertase activity. The qualifier is appropriate, but as a peripheral lumenal subunit EMC7's role is via complex participation, not standalone catalysis.
Reason: Whole-complex molecular function to which EMC7 contributes; EMC7 is non-catalytic (the EMC3/EMC6 vestibule is the catalytic core), so not EMC7's own core MF.
Supporting Evidence:
file:human/EMC7/EMC7-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... 		KEEP AS NON CORE
Summary: IMP evidence (topogenesis study) supporting the EMC's membrane insertase activity, to which EMC7 contributes as a complex subunit. Non-core for the non-catalytic EMC7.
Reason: Whole-complex MF; EMC7 contributes via membership but is not the catalytic subunit.
Supporting Evidence:
file:human/EMC7/EMC7-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; EMC7 participates as a subunit. Genuine EMC process.
Reason: Correct EMC-mediated process EMC7 participates in.
Supporting Evidence:
file:human/EMC7/EMC7-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 EMC7 in the ER membrane. Core compartment.
Reason: Experimentally supported core location.
Supporting Evidence:
file:human/EMC7/EMC7-uniprot.txt
SUBCELLULAR LOCATION: 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... 		ACCEPT
Summary: IMP (topogenesis study) supporting the EMC's role in insertion of stop-transfer membrane-anchor sequences and N-exo topogenesis; EMC7 participates as a subunit. Genuine EMC process.
Reason: Correct EMC-mediated process EMC7 participates in.
Supporting Evidence:
PMID:30415835
G protein-coupled receptors (GPCRs)
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/EMC7/EMC7-uniprot.txt
SUBCELLULAR LOCATION: Endoplasmic reticulum membrane
GO:0072546 EMC complex
IDA
PMID:22119785
Defining human ERAD networks through an integrative mapping ... 		ACCEPT
Summary: Direct experimental identification of EMC7 in the EMC by the foundational ERAD-network mapping study. Core structural identity.
Reason: Core EMC membership; directly demonstrated.
Supporting Evidence:
file:human/EMC7/EMC7-uniprot.txt
Component of the ER membrane protein complex (EMC).
GO:0016020 membrane
NAS
PMID:12975309
The secreted protein discovery initiative (SPDI), a large-sc... 		KEEP AS NON CORE
Summary: Generic membrane localization asserted (NAS) in the secreted-protein discovery initiative bioinformatics survey that first catalogued this transmembrane protein. Correct but generic and superseded by the specific ER membrane localization.
Reason: Correct but generic and based on a bioinformatic transmembrane prediction; the ER membrane term is the informative localization.
Supporting Evidence:
file:human/EMC7/EMC7-uniprot.txt
Single-pass type I membrane protein

Core Functions

Constitutive architectural subunit of the ER membrane protein complex (EMC), contributing as a complex member to the energy-independent insertion of transmembrane domains into the ER membrane.

Molecular Function:
membrane insertase activity
Directly Involved In:
tail-anchored membrane protein insertion into ER membrane protein insertion into ER membrane by stop-transfer membrane-anchor sequence
Cellular Locations:
endoplasmic reticulum membrane
In Complex:
EMC complex
Supporting Evidence:
  • file:human/EMC7/EMC7-uniprot.txt
    Component of the ER membrane protein complex (EMC).
  • PMID:29242231
    EMC is a transmembrane domain insertase

References

PMID:32459176
The architecture of EMC reveals a path for membrane protein insertion.
GO_REF:0000002
Gene Ontology annotation through association of InterPro records with GO terms
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:12975309
The secreted protein discovery initiative (SPDI), a large-scale effort to identify novel human secreted and transmembrane proteins: a bioinformatics assessment.
PMID:22119785
Defining human ERAD networks through an integrative mapping strategy.
  • Affinity-MS ERAD-network mapping that identified the EMC (including EMC7) in human cells and localized it to the ER membrane.
PMID:28514442
Architecture of the human interactome defines protein communities and disease networks.
PMID:28734904
Identifying novel members of the Wntless interactome through genetic and candidate gene approaches.
PMID:29242231
The ER membrane protein complex is a transmembrane domain insertase.
  • EMC is a transmembrane domain insertase that post-translationally inserts tail-anchored membrane proteins.
PMID:29809151
The ER membrane protein complex interacts cotranslationally to enable biogenesis of multipass membrane proteins.
  • The EMC engages multipass membrane protein clients cotranslationally to enable their biogenesis.
PMID:30415835
EMC Is Required to Initiate Accurate Membrane Protein Topogenesis.
  • The EMC sets the N-exo topology of GPCR/multipass first TMDs, initiating accurate topogenesis.
PMID:31286866
Alternative splicing of the Wnt trafficking protein, Wntless and its effects on protein-protein interactions.
PMID:32296183
A reference map of the human binary protein interactome.
PMID:32439656
Structural basis for membrane insertion by the human ER membrane protein complex.
  • Cryo-EM structure of the human EMC; EMC7 is a single-pass type I subunit with a large lumenal domain; the catalytic vestibule is formed by EMC3 and EMC6.
PMID:33961781
Dual proteome-scale networks reveal cell-specific remodeling of the human interactome.
PMID:35287476
The Function, Structure, and Origins of the ER Membrane Protein Complex.
  • Authoritative review of EMC function, structure, and evolution; places EMC7 as a single-pass subunit contributing a transmembrane helix and cytosolic loops to the dynamic front subdomain near the EMC3/EMC6 catalytic vestibule.
PMID:37199759
A selectivity filter in the ER membrane protein complex limits protein misinsertion at the ER.
  • EMC7 is experimentally confirmed as a type I single-pass subunit and contributes conserved hydrophobic cytosolic loops (and a C-terminal amphipathic helix) beneath the EMC hydrophilic vestibule that transiently capture substrate TMDs; EMC7 is required for biogenesis of the tail-anchored client squalene synthase (SQS).
PMID:37957425
EMC rectifies the topology of multipass membrane proteins.
  • The EMC post-translationally rectifies the topology of multipass membrane proteins by inserting terminal/C-terminal TMDs after release from the ribosome-Sec61 complex, a mechanism estimated to apply to ~250 diverse human multipass proteins; EMC7 participates as an EMC subunit.
PMID:32111841
Selective EMC subunits act as molecular tethers of intracellular organelles exploited during viral entry.
  • EMC7 (with EMC4) acts as an ER-late endosome tether supporting SV40 polyomavirus delivery to the ER; EMC7's cytosolic C-terminal tail binds the late-endosomal GTPase Rab7 and EMC7/EMC4 bind the ER SNARE syntaxin-18, and EMC7 depletion blocks SV40 infection.
PMID:38517390
Structural insights into human EMC and its interaction with VDAC.
  • Cryo-EM of human EMC apo and VDAC1-bound states; EMC7's transmembrane helix becomes ordered upon VDAC1 binding and contributes a substantial fraction (~one-third) of the EMC-VDAC1 interface at mitochondria-ER contact sites.
file:human/EMC7/EMC7-uniprot.txt
UniProt entry Q9NPA0 (EMC7_HUMAN), ER membrane protein complex subunit 7
  • Single-pass type I ER membrane EMC subunit with a lumenal beta-sandwich domain; non-catalytic; part of the EMC insertase.

Suggested Questions for Experts

Q: What specific structural or functional contribution does the lumenal beta-sandwich domain of EMC7 make to EMC stability or substrate handling?

Q: Are the EMC7-WLS interactions reported in interactome screens a reflection of EMC client engagement rather than a standalone binding function?

Suggested Experiments

Experiment: Test whether the EMC7 lumenal beta-sandwich domain binds any carbohydrate ligand in vitro to confirm or refute the InterPro-derived carbohydrate-binding annotation.

Experiment: Reconstitute EMC complexes lacking EMC7 to assess its contribution to complex assembly, stability, and insertion efficiency of representative tail-anchored and multipass substrates.

Deep Research

Falcon

(EMC7-deep-research-falcon.md)
this with annotations you find in gene/protein databases, but these can be outdated or inaccurate. Falcon Edison Scientific Literature 43 citations 2 artifacts 2026-06-12T02:22:38.565131
Edison artifact artifact-00 (text/markdown)
## Context ID: pqac-00000041 The human ER membrane protein complex (EMC) architecture and the location of the EMC7 subunit are primarily shown in Figures 1 and (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 EMC7 (UniProt: Q9NPA0; gene: EMC7; synonyms: C11orf3, C15orf24)

0) Target identity verification (critical)

The requested protein corresponds to the human endoplasmic reticulum (ER) membrane protein complex (EMC) subunit 7, commonly called EMC7. In the primary literature and authoritative reviews, the same subunit is also referred to by the legacy human gene symbol C11orf3 and is conserved with a yeast homolog Sop4, supporting that the β€œEMC7” discussed here is the same ER-resident EMC subunit as in UniProt Q9NPA0. (chitwood2019theroleof pages 2-4, chitwood2019theroleof pages 1-2)

1) Key concepts and definitions (current understanding)

1.1 The ER membrane protein complex (EMC)

The EMC is a conserved, abundant ER membrane machinery implicated in membrane protein biogenesis. Its most established biochemical role is as an insertase for certain transmembrane domains (TMDs), with additional roles in later folding/assembly steps for some membrane proteins. (hegde2022thefunctionstructure pages 1-2)

Mechanistically, cryo-EM structures and structure-guided biochemistry support a model in which substrates are handled through a cytosol-facing hydrophilic vestibule located within the membrane and formed primarily by EMC3 and EMC6; insertion is proposed to be aided by features such as local membrane thinning and electrostatic/structural determinants in and around the vestibule. (pleiner2020structuralbasisfor pages 1-3, hegde2022thefunctionstructure pages 13-14)

1.2 What is EMC7?

EMC7 is a subunit of the EMC that contributes structural and regulatory elements rather than being the catalytic core insertase (which is centered on EMC3–EMC6). EMC7 is consistently described as one of the smaller EMC membrane subunits and has an appreciable lumenal domain contributing to the lumenal mass of the complex. (chitwood2019theroleof pages 2-4)

2) EMC7 protein localization, topology, domains, and structure

2.1 Subcellular localization

EMC7 is an ER membrane protein and a constituent of the ER-resident EMC. (bagchi2020selectiveemcsubunits pages 10-11, pleiner2020structuralbasisfor pages 1-3)

2.2 Membrane topology

Multiple experimental lines support that human EMC7 is a type I, single-pass ER membrane protein (lumenal N-terminus, cytosolic C-terminus). In vitro translation/protease protection with N- and C-terminal tags showed protection of the N-terminal tag but protease accessibility of the C-terminal tag, consistent with a single-spanning type I topology. (pleiner2023aselectivityfilter pages 19-23)

Cryo-EM-based models place EMC7’s N-terminus in the lumenal region (with EMC1/EMC4/EMC10) and observe weak density consistent with a flexible transmembrane helix emerging from EMC7’s lumenal domain. (pleiner2020structuralbasisfor pages 1-3)

2.3 Domain organization and placement in EMC architecture

Structural work on human EMC places EMC7 within the L-shaped lumenal region and shows EMC7 contains a Ξ²-sandwich fold (the EMC7 β€œΞ²-sandwich” domain) as part of the lumenal assembly. (pleiner2020structuralbasisfor media 0c26243d, pleiner2020structuralbasisfor media ab1f47b2, pleiner2020structuralbasisfor pages 1-3)

At the membrane-domain level, EMC7 contributes a single transmembrane helix to a more dynamic β€œfront-side” subdomain near the EMC3/EMC6 core, and crosslinking supports EMC7 proximity to EMC3. (hegde2022thefunctionstructure pages 13-14)

3) Primary molecular function: what EMC7 does

EMC7 has no evidence in this corpus for intrinsic catalytic (enzyme) activity; instead, its molecular function is best understood as participation in a multi-subunit insertase/chaperone machine.

3.1 EMC7’s mechanistic role in substrate capture and insertion (TA/single-pass clients)

A major EMC7-specific mechanistic result is that EMC7 contributes conserved hydrophobic cytosolic loop(s) located immediately beneath the EMC hydrophilic vestibule that physically interact with substrate TMDs. These loops likely act as an initial transient capture site during insertion; mutational analysis indicates that hydrophobicity of this region (rather than precise sequence) is important for function. (pleiner2023aselectivityfilter pages 8-10)

Consistent with this, biochemical work (preprint evidence) further emphasizes that EMC7’s cytosolic elements (including a C-terminal amphipathic helix) are required for efficient biogenesis of EMC-dependent tail-anchored substrates such as squalene synthase (SQS); disrupting the amphipathic helix strongly impaired SQS biogenesis and approximated an EMC7 knockout phenotype. (pleiner2022aselectivityfilter pages 5-7)

3.2 EMC7 contribution to the β€œdynamic subunit” environment around the vestibule

In the selectivity-filter model, EMC7 is among subunits whose dynamic transmembrane domains help form a protected environment that allows nascent TMDs to sample the bilayer, contributing to rapid accept/reject decisions during insertion. (pleiner2023aselectivityfilter pages 10-11)

4) Pathways and biological processes influenced by EMC7 (with concrete examples)

4.1 Membrane protein biogenesis and proteostasis in the ER

At the EMC level, the best-supported function is TMD insertion, especially for tail-anchored and certain signal-anchored proteins, plus broader roles in multipass client maturation. (hegde2022thefunctionstructure pages 20-22, hegde2022thefunctionstructure pages 1-2)

A concrete, well-studied mammalian metabolic example is cholesterol homeostasis, where EMC supports biogenesis of sterol-related enzymes including SQS (tail-anchored, weakly hydrophobic TA) and SOAT1 (polytopic ER enzyme), thereby influencing sterol flux and storage. (volkmar2019theermembrane pages 1-3)

EMC7 itself is experimentally required for SQS biogenesis in human cells in the 2023 selectivity-filter study, supporting that EMC7 participates directly in this sterol-pathway node via its role in TA insertion/handling. (pleiner2023aselectivityfilter pages 19-23)

4.2 Post-translational topology rectification of multipass proteins (context for EMC7)

A major recent conceptual advance is that EMC does not only act co-translationally; it can also rectify topology post-translationally by inserting C-terminal/terminal TMDs of multipass membrane proteins after release from the ribosome–Sec61 complex. This mechanism is proposed to apply to approximately ~250 diverse human multipass proteins. (wu2024emcrectifiesthe pages 1-2)

While this 2024 study does not assign a unique catalytic role to EMC7, it substantially expands the set of physiological situations where EMC7-containing EMC complexes are likely required, including biogenesis of pharmacologically important targets such as pentameric ion-channel subunits. (wu2024emcrectifiesthe pages 1-2)

5) Interaction partners and molecular networks

5.1 Within the EMC

Human EMC7’s lumenal domain associates with lumenal EMC architecture (including EMC1/EMC10 in structural studies), and EMC7’s single TMD lies near EMC3/EMC6 in the dynamic front subdomain with crosslinking-based support for proximity to EMC3. (hegde2022thefunctionstructure pages 13-14, pleiner2020structuralbasisfor pages 1-3)

5.2 Non-canonical roles: organelle tethering and viral entry

A distinct EMC7 function reported in cell biology/virology is participation (with EMC4) as an ER–late endosome tether that supports polyomavirus SV40 delivery from late endosomes to the ER.

Mechanistic evidence includes: (i) EMC7 is a type I single-pass ER protein whose cytosolic C-terminal tail contains disordered/low-complexity segments that mediate binding to the late endosomal GTPase Rab7; (ii) EMC7 (and EMC4) also binds the ER SNARE syntaxin18 (Stx18); (iii) depletion of EMC7 blocks SV40 infection by preventing late endosome-to-ER targeting, with quantitative results reported as means Β± SD over three independent experiments (e.g., infections around MOI ~2). (bagchi2020selectiveemcsubunits pages 10-11)

A 2023 expert review synthesizes this as evidence thatβ€”beyond insertase activityβ€”the EMC facilitates ER membrane contact sites (MCSs) with other organelles, highlighting EMC4/EMC7-dependent ER–endosome tethering in SV40 entry. (woo2023howhoster pages 4-5)

5.3 Mitochondria–ER contact sites: EMC7 interaction with VDAC

A 2024 cryo-EM study reports EMC association with VDAC1 at mitochondria–ER contacts and identifies EMC7 as a principal contributor to the binding interface. In the EMC–VDAC1 complex, EMC7’s transmembrane helix becomes ordered (being β€œinvisible” in apo EMC) and contributes roughly one-third of the EMC–VDAC1 interface area; the complex buries ~2,336 Γ…Β² at the interface overall and is supported by in-cell NanoBiT/BiFC assays localizing the association to mitochondria–ER contact sites. (li2024structuralinsightsinto pages 3-5)

6) Recent developments (prioritizing 2023–2024)

6.1 2023: EMC selectivity filter and EMC7’s role in substrate handling

A 2023 Journal of Cell Biology paper presents a selectivity filter framework for the EMC vestibule and assigns EMC7 a role in substrate capture via conserved hydrophobic loops beneath the vestibule. The same work provides experimental confirmation that EMC7 is a type I single-pass subunit and supports its functional requirement for SQS biogenesis. (pleiner2023aselectivityfilter pages 8-10, pleiner2023aselectivityfilter pages 19-23)

6.2 2023: EMC7 in virus entry and ER–endosome MCS biology

A 2023 Journal of Cell Science review emphasizes EMC subunits as multifunctional host factors exploited by viruses and frames EMC7 (with EMC4) as mediating ER–endosome membrane contacts required for SV40 entry. (woo2023howhoster pages 4-5)

6.3 2024: EMC-driven topology rectification for ~250 multipass proteins

A 2024 Nature Structural & Molecular Biology study argues that EMC-mediated post-translational terminal-TMD insertion is a general solution for multipass proteins whose final TMDs are not fully inserted co-translationally, and estimates applicability to ~250 multipass proteins. (wu2024emcrectifiesthe pages 1-2)

6.4 2024: EMC7 as a structural mediator of EMC–VDAC interaction

A 2024 cryo-EM study proposes EMC7-dependent structural switching at mitochondria–ER contact sites, where EMC7’s helix becomes ordered and forms a substantial fraction of the EMC–VDAC interface, potentially modulating EMC’s insertase state. (li2024structuralinsightsinto pages 3-5)

7) Applications and real-world implementations

  1. Antiviral host-factor biology (SV40 model): EMC7 (with EMC4) is directly implicated as a molecular tether promoting late endosome-to-ER delivery of SV40 and efficient infection, via Rab7 and syntaxin18 interactions. This is a concrete, mechanistically dissected example of how an ER biogenesis complex subunit is repurposed for organelle communication and pathogen trafficking. (bagchi2020selectiveemcsubunits pages 10-11)

  2. Membrane-protein biogenesis as a biomedical lever: Because many membrane proteins are drug targets, EMC function (including EMC7-dependent client handling and topology enforcement) is relevant to production/stability of receptors and channels. A 2024 study explicitly highlights pentameric ion channel subunits as substrates in the EMC-dependent topology-rectification mechanism. (wu2024emcrectifiesthe pages 1-2)

  3. Metabolic robustness (cholesterol homeostasis): EMC-dependent SQS and SOAT1 biogenesis provides a mechanistic link between membrane insertion machinery (including EMC7-dependent steps for at least SQS) and cellular adaptation to cholesterol availability. (volkmar2019theermembrane pages 1-3, pleiner2023aselectivityfilter pages 19-23)

8) Human genetics and disease associations (with caution)

8.1 GWAS signal near EMC7 in sickle cell disease HbF variability (2024)

A 2024 GWAS of 520 sickle cell disease subjects reported a genome-wide significant locus at 15q14 with lead SNP rs8182015 (P = 2.07 Γ— 10⁻⁸) described as being near EMC7, identified in analyses of fetal hemoglobin (HbF). The authors present this as a locus near EMC7 and note eQTL links to other nearby genes, so the causal gene is not established. (tsukahara2024identificationofgenetic pages 1-2, tsukahara2024identificationofgenetic pages 5-6)

8.2 OpenTargets aggregated evidence

OpenTargets lists EMC7 associations for several disease ontology terms (e.g., neurodegenerative disease, lysosomal storage disease), driven by functional-screen evidence (e.g., CRISPRi neuronal survival/lysotracker studies linked to PMID 34031600). This is useful for hypothesis generation but should not be interpreted as direct causal genetics without follow-up. (OpenTargets Search: -EMC7)

9) Expert synthesis and analysis (authoritative interpretation)

Across structural, biochemical, and cell-biological data, EMC7 is best annotated as a single-pass ER membrane subunit that helps shape a dynamic, substrate-interacting region of the EMC, with experimentally supported roles in: (i) transient TMD capture via hydrophobic cytosolic loops beneath the hydrophilic vestibule; (ii) supporting biogenesis of at least some EMC-dependent tail-anchored clients (notably SQS); and (iii) non-canonical organelle tethering functions at ER–endosome contacts in SV40 entry. (pleiner2023aselectivityfilter pages 8-10, pleiner2023aselectivityfilter pages 19-23, bagchi2020selectiveemcsubunits pages 10-11)

Recent work suggests EMC7’s conformational plasticity can also be exploited in alternate EMC statesβ€”e.g., binding VDAC1 at mitochondria–ER contacts where EMC7 contributes a substantial fraction of the binding interfaceβ€”supporting a broader view of EMC7 as a regulatory/structural element that can participate in switching EMC between functional modes or cellular contexts. (li2024structuralinsightsinto pages 3-5)

10) Summary table (evidence map)

Category Key points Evidence/citation IDs to support
concept/definition Human EMC7 is the ER membrane protein complex subunit 7, a conserved EMC component; literature also uses the legacy human name C11orf3 and notes the yeast homolog Sop4. EMC7 is not the catalytic insertase core itself, but part of the EMC machine that supports membrane protein biogenesis. (chitwood2019theroleof pages 2-4, chitwood2019theroleof pages 1-2, hegde2022thefunctionstructure pages 1-2)
localization/topology EMC7 is an ER membrane subunit with a lumenal N-terminus and type I single-pass topology; protease-protection experiments support a single membrane span, and cryo-EM places EMC7 in the EMC lumenal/front dynamic region with a flexible TMD. (pleiner2023aselectivityfilter pages 19-23, pleiner2020structuralbasisfor pages 1-3, hegde2022thefunctionstructure pages 13-14)
molecular function/mechanism At the complex level, EMC acts as a co-/post-translational insertase and membrane-protein biogenesis factor using a hydrophilic vestibule centered on EMC3/EMC6. EMC7 contributes a dynamic TMD and cytosolic hydrophobic loops beneath the vestibule that help transiently capture incoming substrate TMDs; an EMC7 C-terminal amphipathic element is functionally important for client biogenesis. (pleiner2020structuralbasisfor pages 1-3, hegde2022thefunctionstructure pages 13-14, pleiner2022aselectivityfilter pages 5-7, pleiner2022aselectivityfilter pages 7-9, pleiner2023aselectivityfilter pages 8-10, pleiner2023aselectivityfilter pages 10-11)
interaction partners Within EMC, EMC7 associates with EMC1 and EMC10 in the lumenal domain and is proximal to EMC3 in the membrane region. Beyond the complex, EMC7 binds Rab7 and syntaxin18/Stx18 in ER-late endosome tethering, and its TMH forms a major interface with VDAC1 at mitochondria-ER contact sites. (li2024structuralinsightsinto pages 3-5, bagchi2020selectiveemcsubunits pages 10-11, hegde2022thefunctionstructure pages 13-14, millervedam2020structuralandmechanistic pages 18-21, pleiner2020structuralbasisfor pages 1-3)
substrates/clients EMC7-specific experiments show it is required for biogenesis of the EMC client squalene synthase (SQS); more broadly, EMC supports clients such as SOAT1 and many multipass membrane proteins, but most substrate assignments are complex-level rather than uniquely EMC7-specific. EMC7 loss can reduce TA clients and retain multipass clients in the ER. (volkmar2019theermembrane pages 1-3, pleiner2023aselectivityfilter pages 19-23, li2024structuralinsightsinto pages 21-25, millervedam2020structuralandmechanistic pages 18-21)
recent 2023-2024 developments 2023: EMC7 was mechanistically assigned a role in early substrate capture/selectivity and experimentally confirmed as a type I single-pass subunit. 2024: EMC7 TMH was shown to become ordered upon VDAC1 binding and to contribute about one-third of the EMC-VDAC1 interface; EMC context was expanded by the finding that EMC rectifies topology of ~250 multipass proteins post-translationally. (pleiner2023aselectivityfilter pages 19-23, pleiner2023aselectivityfilter pages 8-10, pleiner2023aselectivityfilter pages 10-11, li2024structuralinsightsinto pages 3-5, wu2024emcrectifiesthe pages 1-2)
human genetics/clinical Direct disease causality for human EMC7 remains limited. A 2024 GWAS in 520 sickle cell disease subjects identified a genome-wide significant locus near EMC7 for HbF (rs8182015, P=2.07Γ—10⁻⁸), but the paper explicitly supports cautious interpretation because proximity does not prove EMC7 causality. OpenTargets also lists disease associations for EMC7 based largely on functional-screen evidence rather than Mendelian proof. (tsukahara2024identificationofgenetic pages 1-2, tsukahara2024identificationofgenetic pages 3-5, tsukahara2024identificationofgenetic pages 5-6, OpenTargets Search: -EMC7)
applications EMC7 has real-world relevance as part of a host pathway exploited in SV40 entry, where EMC7/EMC4 tether late endosomes to the ER through Rab7 and cooperate with Stx18. At the broader EMC level, this biology matters because EMC governs biogenesis of pharmacologically important membrane proteins, including GPCRs, ion channels, and sterol-homeostasis enzymes. (woo2023howhoster pages 6-7, woo2023howhoster pages 4-5, bagchi2020selectiveemcsubunits pages 10-10, bagchi2020selectiveemcsubunits pages 10-11, bagchi2020selectiveemcsubunits pages 1-2, volkmar2019theermembrane pages 1-3, wu2024emcrectifiesthe pages 1-2)

Table: This table condenses the strongest functional-annotation evidence for human EMC7 (UniProt Q9NPA0), separating EMC7-specific findings from broader complex-level EMC biology. It is useful as a quick reference for function, localization, mechanism, interactions, recent studies, and biomedical relevance.

Key cited source URLs and publication dates (selection)

  • Pleiner et al., Science, 2020-07: β€œStructural basis for membrane insertion by the human ER membrane protein complex.” https://doi.org/10.1126/science.abb5008 (pleiner2020structuralbasisfor pages 1-3)
  • Hegde, Annual Review of Biochemistry, 2022-06: β€œThe function, structure, and origins of the ER membrane protein complex.” https://doi.org/10.1146/annurev-biochem-032620-104553 (hegde2022thefunctionstructure pages 13-14)
  • Pleiner et al., Journal of Cell Biology, 2023-05: β€œA selectivity filter in the ER membrane protein complex limits protein misinsertion at the ER.” https://doi.org/10.1083/jcb.202212007 (pleiner2023aselectivityfilter pages 8-10)
  • Woo et al., Journal of Cell Science, 2023-07: β€œHow host ER membrane chaperones and morphogenic proteins support virus infection.” https://doi.org/10.1242/jcs.261121 (woo2023howhoster pages 4-5)
  • Li et al., Aging (Albany NY), 2024-03: β€œStructural insights into human EMC and its interaction with VDAC.” https://doi.org/10.18632/aging.205660 (li2024structuralinsightsinto pages 3-5)
  • Wu et al., Nature Structural & Molecular Biology, 2024-11: β€œEMC rectifies the topology of multipass membrane proteins.” https://doi.org/10.1038/s41594-023-01120-6 (wu2024emcrectifiesthe pages 1-2)
  • Tsukahara et al., Scientific Reports, 2024-08: β€œIdentification of genetic variants associated with clinical features of sickle cell disease.” https://doi.org/10.1038/s41598-024-70922-5 (tsukahara2024identificationofgenetic pages 1-2)

Notes on evidence limitations

  • The retrieved papers did not explicitly state the UniProt accession Q9NPA0 in-text; UniProt mapping is therefore taken from the provided UniProt record, while literature here supports the same biological entity via subunit name/synonym mapping (EMC7/C11orf3/Sop4). (chitwood2019theroleof pages 2-4)
  • Many substrate/client claims are EMC-complex-level; only a subset are directly tested as EMC7-dependent in the retrieved excerpts (e.g., SQS). (pleiner2023aselectivityfilter pages 19-23, volkmar2019theermembrane pages 1-3)

References

  1. (chitwood2019theroleof pages 2-4): Patrick J. Chitwood and Ramanujan S. Hegde. The role of emc during membrane protein biogenesis. Trends in cell biology, 29 5:371-384, May 2019. URL: https://doi.org/10.1016/j.tcb.2019.01.007, doi:10.1016/j.tcb.2019.01.007. This article has 97 citations and is from a domain leading peer-reviewed journal.

  2. (chitwood2019theroleof pages 1-2): Patrick J. Chitwood and Ramanujan S. Hegde. The role of emc during membrane protein biogenesis. Trends in cell biology, 29 5:371-384, May 2019. URL: https://doi.org/10.1016/j.tcb.2019.01.007, doi:10.1016/j.tcb.2019.01.007. This article has 97 citations and is from a domain leading peer-reviewed journal.

  3. (hegde2022thefunctionstructure pages 1-2): Ramanujan S. Hegde. The function, structure, and origins of the er membrane protein complex. Annual Review of Biochemistry, 91:651-678, Jun 2022. URL: https://doi.org/10.1146/annurev-biochem-032620-104553, doi:10.1146/annurev-biochem-032620-104553. This article has 65 citations and is from a domain leading peer-reviewed journal.

  4. (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.

  5. (hegde2022thefunctionstructure pages 13-14): Ramanujan S. Hegde. The function, structure, and origins of the er membrane protein complex. Annual Review of Biochemistry, 91:651-678, Jun 2022. URL: https://doi.org/10.1146/annurev-biochem-032620-104553, doi:10.1146/annurev-biochem-032620-104553. This article has 65 citations and is from a domain leading peer-reviewed journal.

  6. (bagchi2020selectiveemcsubunits pages 10-11): Parikshit Bagchi, Mauricio Torres, Ling Qi, and Billy Tsai. Selective emc subunits act as molecular tethers of intracellular organelles exploited during viral entry. Nature Communications, Feb 2020. URL: https://doi.org/10.1038/s41467-020-14967-w, doi:10.1038/s41467-020-14967-w. This article has 31 citations and is from a highest quality peer-reviewed journal.

  7. (pleiner2023aselectivityfilter pages 19-23): 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.

  8. (pleiner2020structuralbasisfor media 0c26243d): 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.

  9. (pleiner2020structuralbasisfor media ab1f47b2): 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.

  10. (pleiner2023aselectivityfilter pages 8-10): 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. (pleiner2022aselectivityfilter pages 5-7): Tino Pleiner, Masami Hazu, Giovani Pinton Tomaleri, Vy Nguyen, Kurt Januszyk, and Rebecca M. Voorhees. A selectivity filter in the emc limits protein mislocalization to the er. bioRxiv, Dec 2022. URL: https://doi.org/10.1101/2022.11.29.518402, doi:10.1101/2022.11.29.518402. This article has 2 citations.

  12. (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.

  13. (hegde2022thefunctionstructure pages 20-22): Ramanujan S. Hegde. The function, structure, and origins of the er membrane protein complex. Annual Review of Biochemistry, 91:651-678, Jun 2022. URL: https://doi.org/10.1146/annurev-biochem-032620-104553, doi:10.1146/annurev-biochem-032620-104553. This article has 65 citations and is from a domain leading peer-reviewed journal.

  14. (volkmar2019theermembrane pages 1-3): Norbert Volkmar, Maria-Laetitia Thezenas, Sharon M. Louie, Szymon Juszkiewicz, Daniel K. Nomura, Ramanujan S. Hegde, Benedikt M. Kessler, and John C. Christianson. The er membrane protein complex promotes biogenesis of sterol-related enzymes maintaining cholesterol homeostasis. Journal of Cell Science, Jan 2019. URL: https://doi.org/10.1242/jcs.223453, doi:10.1242/jcs.223453. This article has 121 citations and is from a domain leading peer-reviewed journal.

  15. (wu2024emcrectifiesthe pages 1-2): Haoxi Wu, Luka SmalinskaitΔ—, and Ramanujan S. Hegde. Emc rectifies the topology of multipass membrane proteins. Nature Structural & Molecular Biology, 31:32-41, Nov 2024. URL: https://doi.org/10.1038/s41594-023-01120-6, doi:10.1038/s41594-023-01120-6. This article has 41 citations and is from a highest quality peer-reviewed journal.

  16. (woo2023howhoster pages 4-5): Tai-Ting Woo, Jeffrey M. Williams, and Billy Tsai. How host er membrane chaperones and morphogenic proteins support virus infection. Journal of cell science, Jul 2023. URL: https://doi.org/10.1242/jcs.261121, doi:10.1242/jcs.261121. This article has 12 citations and is from a domain leading peer-reviewed journal.

  17. (li2024structuralinsightsinto pages 3-5): 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.

  18. (tsukahara2024identificationofgenetic pages 1-2): Katharine Tsukahara, Xiao Chang, Frank Mentch, Kim Smith-Whitley, Anita Bhandari, Cindy Norris, Joseph T. Glessner, and Hakon Hakonarson. Identification of genetic variants associated with clinical features of sickle cell disease. Scientific Reports, Aug 2024. URL: https://doi.org/10.1038/s41598-024-70922-5, doi:10.1038/s41598-024-70922-5. This article has 6 citations and is from a peer-reviewed journal.

  19. (tsukahara2024identificationofgenetic pages 5-6): Katharine Tsukahara, Xiao Chang, Frank Mentch, Kim Smith-Whitley, Anita Bhandari, Cindy Norris, Joseph T. Glessner, and Hakon Hakonarson. Identification of genetic variants associated with clinical features of sickle cell disease. Scientific Reports, Aug 2024. URL: https://doi.org/10.1038/s41598-024-70922-5, doi:10.1038/s41598-024-70922-5. This article has 6 citations and is from a peer-reviewed journal.

  20. (OpenTargets Search: -EMC7): Open Targets Query (-EMC7, 5 results). Buniello, A. et al. (2025). Open Targets Platform: facilitating therapeutic hypotheses building in drug discovery. Nucleic Acids Research.

  21. (pleiner2022aselectivityfilter pages 7-9): Tino Pleiner, Masami Hazu, Giovani Pinton Tomaleri, Vy Nguyen, Kurt Januszyk, and Rebecca M. Voorhees. A selectivity filter in the emc limits protein mislocalization to the er. bioRxiv, Dec 2022. URL: https://doi.org/10.1101/2022.11.29.518402, doi:10.1101/2022.11.29.518402. This article has 2 citations.

  22. (millervedam2020structuralandmechanistic pages 18-21): Lakshmi E. Miller-Vedam, Bastian BrΓ€uning, 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.

  23. (li2024structuralinsightsinto pages 21-25): 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.

  24. (tsukahara2024identificationofgenetic pages 3-5): Katharine Tsukahara, Xiao Chang, Frank Mentch, Kim Smith-Whitley, Anita Bhandari, Cindy Norris, Joseph T. Glessner, and Hakon Hakonarson. Identification of genetic variants associated with clinical features of sickle cell disease. Scientific Reports, Aug 2024. URL: https://doi.org/10.1038/s41598-024-70922-5, doi:10.1038/s41598-024-70922-5. This article has 6 citations and is from a peer-reviewed journal.

  25. (woo2023howhoster pages 6-7): Tai-Ting Woo, Jeffrey M. Williams, and Billy Tsai. How host er membrane chaperones and morphogenic proteins support virus infection. Journal of cell science, Jul 2023. URL: https://doi.org/10.1242/jcs.261121, doi:10.1242/jcs.261121. This article has 12 citations and is from a domain leading peer-reviewed journal.

  26. (bagchi2020selectiveemcsubunits pages 10-10): Parikshit Bagchi, Mauricio Torres, Ling Qi, and Billy Tsai. Selective emc subunits act as molecular tethers of intracellular organelles exploited during viral entry. Nature Communications, Feb 2020. URL: https://doi.org/10.1038/s41467-020-14967-w, doi:10.1038/s41467-020-14967-w. This article has 31 citations and is from a highest quality peer-reviewed journal.

  27. (bagchi2020selectiveemcsubunits pages 1-2): Parikshit Bagchi, Mauricio Torres, Ling Qi, and Billy Tsai. Selective emc subunits act as molecular tethers of intracellular organelles exploited during viral entry. Nature Communications, Feb 2020. URL: https://doi.org/10.1038/s41467-020-14967-w, doi:10.1038/s41467-020-14967-w. This article has 31 citations and is from a highest quality peer-reviewed journal.

Artifacts

Citations

  1. hegde2022thefunctionstructure pages 1-2
  2. chitwood2019theroleof pages 2-4
  3. pleiner2023aselectivityfilter pages 19-23
  4. pleiner2020structuralbasisfor pages 1-3
  5. hegde2022thefunctionstructure pages 13-14
  6. pleiner2023aselectivityfilter pages 8-10
  7. pleiner2022aselectivityfilter pages 5-7
  8. pleiner2023aselectivityfilter pages 10-11
  9. volkmar2019theermembrane pages 1-3
  10. wu2024emcrectifiesthe pages 1-2
  11. bagchi2020selectiveemcsubunits pages 10-11
  12. woo2023howhoster pages 4-5
  13. li2024structuralinsightsinto pages 3-5
  14. tsukahara2024identificationofgenetic pages 1-2
  15. chitwood2019theroleof pages 1-2
  16. hegde2022thefunctionstructure pages 20-22
  17. tsukahara2024identificationofgenetic pages 5-6
  18. pleiner2022aselectivityfilter pages 7-9
  19. millervedam2020structuralandmechanistic pages 18-21
  20. li2024structuralinsightsinto pages 21-25
  21. tsukahara2024identificationofgenetic pages 3-5
  22. woo2023howhoster pages 6-7
  23. bagchi2020selectiveemcsubunits pages 10-10
  24. bagchi2020selectiveemcsubunits pages 1-2
  25. https://doi.org/10.1126/science.abb5008
  26. https://doi.org/10.1146/annurev-biochem-032620-104553
  27. https://doi.org/10.1083/jcb.202212007
  28. https://doi.org/10.1242/jcs.261121
  29. https://doi.org/10.18632/aging.205660
  30. https://doi.org/10.1038/s41594-023-01120-6
  31. https://doi.org/10.1038/s41598-024-70922-5
  32. https://doi.org/10.1016/j.tcb.2019.01.007,
  33. https://doi.org/10.1146/annurev-biochem-032620-104553,
  34. https://doi.org/10.1126/science.abb5008,
  35. https://doi.org/10.1038/s41467-020-14967-w,
  36. https://doi.org/10.1083/jcb.202212007,
  37. https://doi.org/10.1101/2022.11.29.518402,
  38. https://doi.org/10.1242/jcs.223453,
  39. https://doi.org/10.1038/s41594-023-01120-6,
  40. https://doi.org/10.1242/jcs.261121,
  41. https://doi.org/10.18632/aging.205660,
  42. https://doi.org/10.1038/s41598-024-70922-5,
  43. https://doi.org/10.1101/2020.09.02.280008,

πŸ“š Additional Documentation

Notes

(EMC7-notes.md)

EMC7 (Q9NPA0) review notes

Identity and structure

EMC7 (Endoplasmic reticulum membrane protein complex subunit 7; synonyms C11orf3, C15orf24, HT022, UNQ905/PRO1926) is a 242-aa single-pass type I membrane protein of the ER and a constitutive subunit of the ER membrane protein complex (EMC).

  • Topology (from UniProt FT, PMID:32439656): signal peptide 1-23 (cleaved after Ser-23), lumenal domain 24-159, single transmembrane helix 160-180, cytoplasmic tail 181-242 (with a disordered/low-complexity C-terminus 217-242).
  • [file:human/EMC7/EMC7-uniprot.txt "TOPO_DOM 24..159"], [file:human/EMC7/EMC7-uniprot.txt "Lumenal"], [file:human/EMC7/EMC7-uniprot.txt "TRANSMEM 160..180"].
  • The lumenal portion forms a beta-sandwich ("Beta_sandwich_EMC7", Pfam PF09430 EMC7_beta-sandw; SUPFAM "Starch-binding domain-like"). This carbohydrate-binding-like fold is the basis of the IEA carbohydrate binding annotation, but there is no evidence EMC7 actually binds carbohydrate; the fold is structural.
  • [file:human/EMC7/EMC7-uniprot.txt "Beta_sandwich_EMC7"], [file:human/EMC7/EMC7-uniprot.txt "Starch-binding domain-like"].
  • Belongs to the EMC7 family. [file:human/EMC7/EMC7-uniprot.txt "Belongs to the EMC7 family."]

Core role: EMC complex membership + ER membrane localization

EMC7 is one of ~9 subunits of the EMC, a conserved co- and post-translational transmembrane-domain insertase/chaperone of the ER that inserts newly synthesized membrane proteins energy-independently.

  • EMC complex membership: [file:human/EMC7/EMC7-uniprot.txt "Component of the ER membrane protein complex (EMC)."]; experimentally identified in the EMC by affinity proteomics PMID:22119785 and present in cryo-EM EMC structures [PMID:32439656, PMID:32459176].
  • Subcellular location: [file:human/EMC7/EMC7-uniprot.txt "Endoplasmic reticulum membrane"]; [file:human/EMC7/EMC7-uniprot.txt "Single-pass type I membrane protein"].
  • EMC function (whole-complex): [file:human/EMC7/EMC7-uniprot.txt "enables the energy-independent insertion into endoplasmic\nCC reticulum membranes of newly synthesized membrane proteins"]; required for cotranslational insertion of multipass membrane proteins and post-translational insertion of tail-anchored (TA) proteins [file:human/EMC7/EMC7-uniprot.txt "required for the\nCC post-translational insertion of tail-anchored/TA proteins in\nCC endoplasmic reticulum membranes"].

EMC7 is a LUMENAL, NON-CATALYTIC subunit

The catalytic insertase machinery (hydrophilic vestibule) is formed by EMC3 and EMC6 in the membrane (PMID:32439656 abstract: "occurs via an enclosed hydrophilic vestibule within the membrane formed by the subunits EMC3 and EMC6"). EMC7's bulk is a lumenal beta-sandwich plus one TM helix; it is a peripheral/architectural subunit, not the catalytic core.

Therefore for EMC7:
- CORE = EMC complex membership (GO:0072546) + ER membrane (GO:0005789).
- The insertase molecular function annotations (GO:0032977 membrane insertase activity, contributes_to) and the BP insertion terms (GO:0045050, GO:0071816) describe the whole-complex activity to which EMC7 contributes; they are correct (note contributes_to qualifier is appropriate for a complex member) but the insertase MF should NOT be elevated to EMC7's own core catalytic function. Keep BP insertion terms as genuine EMC-mediated processes EMC7 is involved in.

protein binding (GO:0005515, IPI) entries

Eight IPI protein-binding annotations from interactome/IntAct screens. Per CLAUDE.md, bare protein binding is uninformative -> KEEP_AS_NON_CORE. Partners are recorded in the UniProt IntAct block and in the goa WITH/FROM column:
- PMID:28514442 -> PDIA4 (P13667). [file:human/EMC7/EMC7-uniprot.txt "P13667: PDIA4"]
- PMID:28734904 (Wntless interactome) -> WLS (Q5T9L3-1). [file:human/EMC7/EMC7-uniprot.txt "Q5T9L3-1: WLS"]
- PMID:31286866 (Wntless splicing/PPI) -> WLS (Q5T9L3-1). [file:human/EMC7/EMC7-uniprot.txt "Q5T9L3-1: WLS"]
- PMID:32296183 (HuRI binary interactome) -> CYSRT1 (A8MQ03), NOTCH2NLC (P0DPK4), KRTAP5-9 (P26371), KRTAP1-1 (Q07627), MEOX2 (Q6FHY5), KRTAP5-2 (Q701N4). [file:human/EMC7/EMC7-uniprot.txt "A8MQ03: CYSRT1"]
- PMID:33961781 (BioPlex) -> PDIA4 (P13667). [file:human/EMC7/EMC7-uniprot.txt "P13667: PDIA4"]

WLS (Wntless) is itself an EMC substrate/client, so the WLS interactions plausibly reflect EMC client engagement; the HuRI keratin-associated-protein hits are likely sticky binary Y2H artifacts. None elevate to core; all KEEP_AS_NON_CORE.

carbohydrate binding (GO:0030246, IEA InterPro)

From the SUPFAM "Starch-binding domain-like"/carbohydrate-binding-like fold (IPR013784). This is a fold-homology electronic inference with no experimental support; EMC7 is not known to bind carbohydrate. Over-propagated IEA -> MARK_AS_OVER_ANNOTATED (or REMOVE-candidate). Using MARK_AS_OVER_ANNOTATED to be conservative.

membrane (GO:0016020, IDA/NAS)

Generic "membrane" β€” correct but less informative than ER membrane (GO:0005789). KEEP_AS_NON_CORE / MODIFY to ER membrane is debatable; the IDA (PMID:22119785) is real but generic. Keep as non-core (parent of the specific ER membrane term).

Annotation tally (21 in goa, deduped from goa.tsv rows 2-28; stub has 21 entries)

  • EMC complex (GO:0072546): IBA, IPI (PMID:32439656), IDA (PMID:22119785) β€” all ACCEPT (CORE).
  • ER membrane (GO:0005789): IEA, NAS (PMID:29242231), EXP (PMID:22119785), IDA (PMID:32439656) β€” ACCEPT (CORE).
  • carbohydrate binding (GO:0030246): IEA β€” MARK_AS_OVER_ANNOTATED.
  • protein binding (GO:0005515) x6 IPI rows in stub β€” KEEP_AS_NON_CORE.
  • membrane insertase activity (GO:0032977) x2 IMP contributes_to β€” KEEP_AS_NON_CORE (whole-complex MF; EMC7 non-catalytic, contributes_to qualifier appropriate).
  • protein insertion by stop-transfer (GO:0045050) IDA + 2x IMP β€” ACCEPT (EMC process; non-core relative to complex membership but a genuine function).
  • tail-anchored insertion (GO:0071816) IDA β€” ACCEPT (EMC process).
  • membrane (GO:0016020) IDA + NAS β€” KEEP_AS_NON_CORE (generic).

References to verify

All EMC mechanism papers (29242231, 29809151, 30415835, 32439656) have cached full text (32439656 abstract-only). Interaction papers all cached. Per guidelines, do not REMOVE experimental IMP/IDA/IPI just because a cached abstract foregrounds the whole complex; these are complex-member annotations and are appropriate.

Falcon deep-research findings (incorporated 2026-06)

  • EMC7-specific substrate-capture role: EMC7 contributes conserved hydrophobic cytosolic loops (and a C-terminal amphipathic helix) beneath the EMC hydrophilic vestibule that transiently capture incoming substrate TMDs; hydrophobicity (not exact sequence) matters PMID:37199759. PMID verified via PubMed.
  • EMC7 confirmed as a type I single-pass subunit (lumenal N-terminus, cytosolic C-terminus) by protease-protection, and is experimentally required for biogenesis of the tail-anchored client squalene synthase (SQS) PMID:37199759. This is the most direct EMC7-specific functional evidence and now also added to the core_function supported_by.
  • Post-translational topology rectification: EMC inserts terminal/C-terminal TMDs of multipass proteins after ribosome-Sec61 release, estimated to apply to ~250 human multipass proteins; expands EMC-dependent processes EMC7-containing complexes participate in (complex-level) PMID:37957425. PMID verified.
  • Non-canonical organelle tethering: EMC7 (with EMC4) tethers ER to late endosomes during SV40 polyomavirus entry; the cytosolic C-terminal tail binds Rab7, and EMC7/EMC4 bind ER SNARE syntaxin-18 (Stx18); EMC7 depletion blocks SV40 infection PMID:32111841. PMID verified. This is an EMC7-specific (cytosolic-tail-mediated) function distinct from insertase activity.
  • ER-mitochondria contact role: in the EMC-VDAC1 cryo-EM structure, EMC7's TMH becomes ordered upon VDAC1 binding and forms ~one-third of the EMC-VDAC1 interface at mitochondria-ER contact sites PMID:38517390. PMID verified (Aging Albany NY 2024).
  • Authoritative review framing (Hegde 2022) places EMC7 contributing a TMH and cytosolic loops to the dynamic front subdomain near the EMC3/EMC6 catalytic vestibule; non-catalytic architectural/regulatory subunit PMID:35287476. PMID verified.
  • Note (not added to YAML): a 2024 sickle-cell GWAS reports a genome-wide-significant HbF locus at 15q14 "near EMC7" (rs8182015), but the authors caution proximity does not establish EMC7 causality; left out of annotations as it does not establish EMC7 function.

Pn Notes

(EMC7-pn-notes.md)

EMC7 PN Consistency Notes

  • Generated: 2026-06-18
  • Project: PROTEOSTASIS
  • Scope: PN consistency rereview against local AIGR review and available deep-research artifacts
  • UniProt: Q9NPA0
  • 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: EMC7 (ER membrane protein complex subunit 7) is a 242 aa single-pass type I ER membrane protein and a constitutive subunit of the ER membrane protein complex (EMC), a conserved transmembrane-domain insertase and membrane-protein chaperone of the endoplasmic reticulum. After cleavage of its N-terminal signal peptide, EMC7 presents a large lumenal beta-sandwich domain followed by a single transmembrane helix and a short, partly disordered cytoplasmic tail. EMC7 is a peripheral, non-catalytic architectural subunit; the catalytic insertase machinery (the membrane-embedded hydrophilic vestibule) is formed by EMC3 and EMC6. As part of the EMC, EMC7 contributes to the energy-independent insertion of newly synthesized membrane proteins into the ER membrane, with a preference for transmembrane domains that are weakly hydrophobic or contain destabilizing residues, including post-translational insertion of tail-anchored proteins and cotranslational insertion and topogenesis of multipass membrane proteins. EMC7 localizes to the ER membrane and is broadly expressed.
  • Existing/core annotation action counts: ACCEPT: 11; KEEP_AS_NON_CORE: 9; MARK_AS_OVER_ANNOTATED: 1

PN Consistency Summary

  • Consistency: Deep research (notes + falcon), review YAML, PN annotation, and the type-level mapping are mutually consistent. EMC7 is a single-pass type I, non-catalytic architectural EMC subunit (lumenal beta-sandwich; catalytic vestibule = EMC3/EMC6). No contradictions. The review additionally documents EMC7-specific roles (Rab7/syntaxin-18 ER–endosome tethering, PMID:32111841; VDAC1 interface, PMID:38517390; SQS-client selectivity filter, PMID:37199759) absent from the dossier, but these elaborate rather than conflict.
  • PN story / NEW pressure: PN asserts only EMC membership + ER membrane-protein import/insertion, all already captured (GO:0072546 part_of; GO:0045050, GO:0071816, GO:0032977 contributes_to). No NEW GO term needed. The carbohydrate-binding IEA (GO:0030246) is correctly MARK_AS_OVER_ANNOTATED. EMC7's tethering/VDAC moonlighting is not pushed as a PN role.
  • Evidence alignment: Strong overlap β€” both cite the EMC insertase/structure literature; the review's PMIDs (22119785, 29242231, 32439656, 30415835, etc.) fully cover the PN process claim.
  • Verdict: Consistent; well-reviewed. Sole concern is the group-level GO:0044743 import mapping (shared across EMC7-10), which mismatches EMC "insertion" semantics.

Full Consistency Review

  • UniProt: Q9NPA0 Β· batch: proteostasis-batch-2026-06-11 Β· review status: COMPLETE
  • PN placement: ER proteostasis|Protein transport|Transmembrane protein import|EMC complex component ; PN-node mapping: type=mapped/ok_for_propagation β†’ GO:0072546 (EMC complex); group β†’ GO:0044743 (protein transmembrane import into intracellular organelle); class β†’ GO:0015031 (protein transport); branch=no_mapping.
  • Consistency: Deep research (notes + falcon), review YAML, PN annotation, and the type-level mapping are mutually consistent. EMC7 is a single-pass type I, non-catalytic architectural EMC subunit (lumenal beta-sandwich; catalytic vestibule = EMC3/EMC6). No contradictions. The review additionally documents EMC7-specific roles (Rab7/syntaxin-18 ER–endosome tethering, PMID:32111841; VDAC1 interface, PMID:38517390; SQS-client selectivity filter, PMID:37199759) absent from the dossier, but these elaborate rather than conflict.
  • PN story / NEW pressure: PN asserts only EMC membership + ER membrane-protein import/insertion, all already captured (GO:0072546 part_of; GO:0045050, GO:0071816, GO:0032977 contributes_to). No NEW GO term needed. The carbohydrate-binding IEA (GO:0030246) is correctly MARK_AS_OVER_ANNOTATED. EMC7's tethering/VDAC moonlighting is not pushed as a PN role.
  • Mapping strategy: EMC7 does not change the shared EMC-node mapping. Typeβ†’GO:0072546 is exact and correct. The groupβ†’GO:0044743 is semantically off: GO:0044743 (def. "directed movement of proteins into an intracellular organelle, across a membrane") is lumenal import (TOM/TIM-type), whereas the EMC performs membrane-protein insertion; GO:0071816/GO:0045050 (via GO:0090150 establishment of protein localization to membrane) are NOT subclasses of GO:0044743. GO:0044743 over-reaches/diverges.
  • Evidence alignment: Strong overlap β€” both cite the EMC insertase/structure literature; the review's PMIDs (22119785, 29242231, 32439656, 30415835, etc.) fully cover the PN process claim.
  • Verdict: Consistent; well-reviewed. Sole concern is the group-level GO:0044743 import mapping (shared across EMC7-10), which mismatches EMC "insertion" semantics.

PN Dossier Context

  • review_batch: proteostasis-batch-2026-06-11
  • review_yaml: genes/human/EMC7/EMC7-ai-review.yaml
  • PN workbook rows: 1

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

  • UniProt: Q9NPA0
  • 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.

πŸ“„ View Raw YAML

 
id: Q9NPA0
gene_symbol: EMC7
product_type: PROTEIN
status: COMPLETE
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: EMC7 (ER membrane protein complex subunit 7) is a 242 aa single-pass type I ER membrane protein and a constitutive subunit of the ER membrane protein complex (EMC), a conserved transmembrane-domain insertase and membrane-protein chaperone of the endoplasmic reticulum. After cleavage of its N-terminal signal peptide, EMC7 presents a large lumenal beta-sandwich domain followed by a single transmembrane helix and a short, partly disordered cytoplasmic tail. EMC7 is a peripheral, non-catalytic architectural subunit; the catalytic insertase machinery (the membrane-embedded hydrophilic vestibule) is formed by EMC3 and EMC6. As part of the EMC, EMC7 contributes to the energy-independent insertion of newly synthesized membrane proteins into the ER membrane, with a preference for transmembrane domains that are weakly hydrophobic or contain destabilizing residues, including post-translational insertion of tail-anchored proteins and cotranslational insertion and topogenesis of multipass membrane proteins. EMC7 localizes to the ER membrane and is broadly expressed.
existing_annotations:
- term:
    id: GO:0072546
    label: EMC complex
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: part_of
  review:
    summary: Phylogenetic assignment of EMC complex membership, consistent with direct experimental and structural identification of EMC7 in the EMC. This is the core structural identity of EMC7.
    action: ACCEPT
    reason: EMC complex membership is the core cellular-component identity of EMC7; supported by IDA, cryo-EM, and the conserved EMC7 family.
    supported_by:
    - reference_id: file:human/EMC7/EMC7-uniprot.txt
      supporting_text: Component of the ER membrane protein complex (EMC).
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: Electronic transfer of the ER membrane subcellular location from UniProt; the correct and core compartment for EMC7.
    action: ACCEPT
    reason: Correct core location; redundant with experimental EXP/IDA evidence.
    supported_by:
    - reference_id: file:human/EMC7/EMC7-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Endoplasmic reticulum membrane'
- term:
    id: GO:0030246
    label: carbohydrate binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: enables
  review:
    summary: InterPro fold-homology assignment derived from the lumenal beta-sandwich resembling a starch-binding/carbohydrate-binding-like domain. There is no experimental evidence that EMC7 binds carbohydrate; the fold is structural and the assignment is an over-propagated electronic inference.
    action: MARK_AS_OVER_ANNOTATED
    reason: Fold-similarity-only IEA with no supporting evidence that EMC7 actually binds carbohydrate; the beta-sandwich is structural and serves complex architecture.
    supported_by:
    - reference_id: file:human/EMC7/EMC7-uniprot.txt
      supporting_text: Starch-binding domain-like
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:28514442
  qualifier: enables
  review:
    summary: High-throughput interactome capture (with PDIA4). Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: High-throughput interaction; bare protein binding is uninformative per guidelines.
    supported_by:
    - reference_id: file:human/EMC7/EMC7-uniprot.txt
      supporting_text: 'P13667: PDIA4'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:28734904
  qualifier: enables
  review:
    summary: Interaction with WLS (Wntless), itself an EMC client, identified in a Wntless-interactome screen. The interaction plausibly reflects EMC client engagement, but bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: Likely reflects client engagement, but the bare term is uninformative and not core.
    supported_by:
    - reference_id: file:human/EMC7/EMC7-uniprot.txt
      supporting_text: 'Q5T9L3-1: WLS'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:31286866
  qualifier: enables
  review:
    summary: Interaction with WLS from a Wntless splicing/PPI study. WLS is an EMC client; bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: Likely client engagement; bare term uninformative, not core.
    supported_by:
    - reference_id: file:human/EMC7/EMC7-uniprot.txt
      supporting_text: 'Q5T9L3-1: WLS'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:32296183
  qualifier: enables
  review:
    summary: High-throughput binary (HuRI) interactome captures (CYSRT1, NOTCH2NLC, keratin-associated proteins, MEOX2); several are likely sticky Y2H hits. Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: High-throughput binary interactions of uncertain biological relevance; bare term uninformative.
    supported_by:
    - reference_id: file:human/EMC7/EMC7-uniprot.txt
      supporting_text: 'A8MQ03: CYSRT1'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:33961781
  qualifier: enables
  review:
    summary: BioPlex affinity-MS interactome capture (with PDIA4). Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: High-throughput interaction; bare term uninformative, not core.
    supported_by:
    - reference_id: file:human/EMC7/EMC7-uniprot.txt
      supporting_text: 'P13667: PDIA4'
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: NAS
  original_reference_id: PMID:29242231
  qualifier: located_in
  review:
    summary: ComplexPortal NAS annotation of ER membrane localization for the EMC, consistent with experimental evidence. Core compartment.
    action: ACCEPT
    reason: Correct core location; consistent with EXP/IDA evidence.
    supported_by:
    - reference_id: file:human/EMC7/EMC7-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Endoplasmic reticulum membrane'
- term:
    id: GO:0045050
    label: protein insertion into ER membrane by stop-transfer membrane-anchor sequence
  evidence_type: IDA
  original_reference_id: PMID:29242231
  qualifier: involved_in
  review:
    summary: The EMC inserts transmembrane domains, including stop-transfer membrane-anchor sequences of multipass proteins; EMC7 participates as an EMC subunit. A genuine EMC-mediated process, though EMC7 is non-catalytic.
    action: ACCEPT
    reason: Correct EMC-mediated process EMC7 is involved in as a complex subunit; non-core relative to complex membership.
    supported_by:
    - reference_id: PMID:29242231
      supporting_text: EMC is a transmembrane domain insertase
- term:
    id: GO:0071816
    label: tail-anchored membrane protein insertion into ER membrane
  evidence_type: IDA
  original_reference_id: PMID:29242231
  qualifier: involved_in
  review:
    summary: The EMC mediates post-translational insertion of tail-anchored proteins; EMC7 participates as an EMC subunit. Genuine EMC-mediated process.
    action: ACCEPT
    reason: Correct EMC-mediated process EMC7 participates in via membership.
    supported_by:
    - reference_id: PMID:29242231
      supporting_text: tail-anchored membrane proteins with moderately hydrophobic transmembrane
- term:
    id: GO:0072546
    label: EMC complex
  evidence_type: IPI
  original_reference_id: PMID:32439656
  qualifier: part_of
  review:
    summary: ComplexPortal IPI assignment of EMC complex membership based on the cryo-EM structure of the human EMC. Core structural identity of EMC7.
    action: ACCEPT
    reason: Structurally demonstrated core EMC membership.
    supported_by:
    - reference_id: file:human/EMC7/EMC7-uniprot.txt
      supporting_text: Component of the ER membrane protein complex (EMC).
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: EXP
  original_reference_id: PMID:22119785
  qualifier: located_in
  review:
    summary: Experimental ER membrane localization from the EMC-discovery ERAD-network study. Core compartment.
    action: ACCEPT
    reason: Experimentally supported core location.
    supported_by:
    - reference_id: file:human/EMC7/EMC7-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Endoplasmic reticulum membrane'
- term:
    id: GO:0032977
    label: membrane insertase activity
  evidence_type: IMP
  original_reference_id: PMID:29809151
  qualifier: contributes_to
  review:
    summary: IMP evidence that EMC subunit depletion impairs membrane insertion; EMC7 contributes_to the complex insertase activity. The qualifier is appropriate, but as a peripheral lumenal subunit EMC7's role is via complex participation, not standalone catalysis.
    action: KEEP_AS_NON_CORE
    reason: Whole-complex molecular function to which EMC7 contributes; EMC7 is non-catalytic (the EMC3/EMC6 vestibule is the catalytic core), so not EMC7's own core MF.
    supported_by:
    - reference_id: file:human/EMC7/EMC7-uniprot.txt
      supporting_text: enables the energy-independent insertion into endoplasmic
- term:
    id: GO:0032977
    label: membrane insertase activity
  evidence_type: IMP
  original_reference_id: PMID:30415835
  qualifier: contributes_to
  review:
    summary: IMP evidence (topogenesis study) supporting the EMC's membrane insertase activity, to which EMC7 contributes as a complex subunit. Non-core for the non-catalytic EMC7.
    action: KEEP_AS_NON_CORE
    reason: Whole-complex MF; EMC7 contributes via membership but is not the catalytic subunit.
    supported_by:
    - reference_id: file:human/EMC7/EMC7-uniprot.txt
      supporting_text: enables the energy-independent insertion into endoplasmic
- term:
    id: GO:0045050
    label: protein insertion into ER membrane by stop-transfer membrane-anchor sequence
  evidence_type: IMP
  original_reference_id: PMID:29809151
  qualifier: involved_in
  review:
    summary: The EMC is required for cotranslational insertion of multipass proteins in which stop-transfer membrane-anchor sequences become membrane-spanning helices; EMC7 participates as a subunit. Genuine EMC process.
    action: ACCEPT
    reason: Correct EMC-mediated process EMC7 participates in.
    supported_by:
    - reference_id: file:human/EMC7/EMC7-uniprot.txt
      supporting_text: stop-transfer membrane-anchor sequences become ER membrane spanning
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: IDA
  original_reference_id: PMID:32439656
  qualifier: located_in
  review:
    summary: Direct (structural) evidence placing EMC7 in the ER membrane. Core compartment.
    action: ACCEPT
    reason: Experimentally supported core location.
    supported_by:
    - reference_id: file:human/EMC7/EMC7-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Endoplasmic reticulum membrane'
- term:
    id: GO:0045050
    label: protein insertion into ER membrane by stop-transfer membrane-anchor sequence
  evidence_type: IMP
  original_reference_id: PMID:30415835
  qualifier: involved_in
  review:
    summary: IMP (topogenesis study) supporting the EMC's role in insertion of stop-transfer membrane-anchor sequences and N-exo topogenesis; EMC7 participates as a subunit. Genuine EMC process.
    action: ACCEPT
    reason: Correct EMC-mediated process EMC7 participates in.
    supported_by:
    - reference_id: PMID:30415835
      supporting_text: G protein-coupled receptors (GPCRs)
- term:
    id: GO:0016020
    label: membrane
  evidence_type: IDA
  original_reference_id: PMID:22119785
  qualifier: located_in
  review:
    summary: Direct generic membrane localization from the EMC-discovery study; a parent of the specific ER membrane term.
    action: KEEP_AS_NON_CORE
    reason: Correct but generic; the ER membrane term captures the informative localization.
    supported_by:
    - reference_id: file:human/EMC7/EMC7-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Endoplasmic reticulum membrane'
- term:
    id: GO:0072546
    label: EMC complex
  evidence_type: IDA
  original_reference_id: PMID:22119785
  qualifier: part_of
  review:
    summary: Direct experimental identification of EMC7 in the EMC by the foundational ERAD-network mapping study. Core structural identity.
    action: ACCEPT
    reason: Core EMC membership; directly demonstrated.
    supported_by:
    - reference_id: file:human/EMC7/EMC7-uniprot.txt
      supporting_text: Component of the ER membrane protein complex (EMC).
- term:
    id: GO:0016020
    label: membrane
  evidence_type: NAS
  original_reference_id: PMID:12975309
  qualifier: located_in
  review:
    summary: Generic membrane localization asserted (NAS) in the secreted-protein discovery initiative bioinformatics survey that first catalogued this transmembrane protein. Correct but generic and superseded by the specific ER membrane localization.
    action: KEEP_AS_NON_CORE
    reason: Correct but generic and based on a bioinformatic transmembrane prediction; the ER membrane term is the informative localization.
    supported_by:
    - reference_id: file:human/EMC7/EMC7-uniprot.txt
      supporting_text: Single-pass type I membrane protein
references:
- id: PMID:32459176
  title: The architecture of EMC reveals a path for membrane protein insertion.
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: 'O''Donnell et al. 2020 (eLife). Cryo-EM architecture of the human EMC,
      establishing the overall complex organization and subunit topology relevant to
      EMC7 as a constitutive EMC subunit.'
- id: GO_REF:0000002
  title: Gene Ontology annotation through association of InterPro records with GO terms
  findings: []
- id: GO_REF:0000033
  title: Annotation inferences using phylogenetic trees
  findings: []
- id: GO_REF:0000044
  title: Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location vocabulary mapping, accompanied by conservative changes to GO terms applied by UniProt
  findings: []
- id: PMID:12975309
  title: 'The secreted protein discovery initiative (SPDI), a large-scale effort to identify novel human secreted and transmembrane proteins: a bioinformatics assessment.'
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: Bioinformatic transmembrane-protein survey; source of a generic NAS membrane annotation.
- id: PMID:22119785
  title: Defining human ERAD networks through an integrative mapping strategy.
  findings:
  - statement: Affinity-MS ERAD-network mapping that identified the EMC (including EMC7) in human cells and localized it to the ER membrane.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Foundational identification of the human EMC; source of EMC membership and ER membrane localization for EMC7.
- id: PMID:28514442
  title: Architecture of the human interactome defines protein communities and disease networks.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: High-throughput interactome (PDIA4 partner); bare protein binding.
- id: PMID:28734904
  title: Identifying novel members of the Wntless interactome through genetic and candidate gene approaches.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: WLS (Wntless, an EMC client) interaction; plausibly client engagement.
- id: PMID:29242231
  title: The ER membrane protein complex is a transmembrane domain insertase.
  findings:
  - statement: EMC is a transmembrane domain insertase that post-translationally inserts tail-anchored membrane proteins.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Establishes the EMC insertase function; basis for insertion BP annotations.
- id: PMID:29809151
  title: The ER membrane protein complex interacts cotranslationally to enable biogenesis of multipass membrane proteins.
  findings:
  - statement: The EMC engages multipass membrane protein clients cotranslationally to enable their biogenesis.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: Cotranslational multipass biogenesis role of the EMC.
- id: PMID:30415835
  title: EMC Is Required to Initiate Accurate Membrane Protein Topogenesis.
  findings:
  - statement: The EMC sets the N-exo topology of GPCR/multipass first TMDs, initiating accurate topogenesis.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Topogenesis role of the EMC.
- id: PMID:31286866
  title: Alternative splicing of the Wnt trafficking protein, Wntless and its effects on protein-protein interactions.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: WLS interaction; plausibly EMC client engagement.
- id: PMID:32296183
  title: A reference map of the human binary protein interactome.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: HuRI binary interactome; several likely sticky Y2H hits (keratin-associated proteins).
- id: PMID:32439656
  title: Structural basis for membrane insertion by the human ER membrane protein complex.
  findings:
  - statement: Cryo-EM structure of the human EMC; EMC7 is a single-pass type I subunit with a large lumenal domain; the catalytic vestibule is formed by EMC3 and EMC6.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Structural placement of EMC7 and topology; abstract-only in cache.
- id: PMID:33961781
  title: Dual proteome-scale networks reveal cell-specific remodeling of the human interactome.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: BioPlex interactome (PDIA4 partner); bare protein binding.
- id: PMID:35287476
  title: The Function, Structure, and Origins of the ER Membrane Protein Complex.
  findings:
  - statement: Authoritative review of EMC function, structure, and evolution; places EMC7 as a single-pass subunit contributing a transmembrane helix and cytosolic loops to the dynamic front subdomain near the EMC3/EMC6 catalytic vestibule.
    reference_section_type: LITERATURE_REVIEW
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: PubMed-verified (Annu Rev Biochem 2022). Review synthesizing EMC architecture and mechanism; supports the structural placement and non-catalytic role of EMC7 already described in the review.
- id: PMID:37199759
  title: A selectivity filter in the ER membrane protein complex limits protein misinsertion at the ER.
  findings:
  - statement: EMC7 is experimentally confirmed as a type I single-pass subunit and contributes conserved hydrophobic cytosolic loops (and a C-terminal amphipathic helix) beneath the EMC hydrophilic vestibule that transiently capture substrate TMDs; EMC7 is required for biogenesis of the tail-anchored client squalene synthase (SQS).
    reference_section_type: ABSTRACT
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: PubMed-verified (J Cell Biol 2023, PMID:37199759). Provides EMC7-specific mechanistic evidence for a substrate-capture/selectivity-filter role and confirms type I single-pass topology and SQS-client dependence.
- id: PMID:37957425
  title: EMC rectifies the topology of multipass membrane proteins.
  findings:
  - statement: The EMC post-translationally rectifies the topology of multipass membrane proteins by inserting terminal/C-terminal TMDs after release from the ribosome-Sec61 complex, a mechanism estimated to apply to ~250 diverse human multipass proteins; EMC7 participates as an EMC subunit.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: PubMed-verified (Nat Struct Mol Biol 2024, PMID:37957425). Expands the set of EMC-dependent processes (post-translational topology rectification) in which EMC7-containing complexes participate; complex-level, not EMC7-specific catalysis.
- id: PMID:32111841
  title: Selective EMC subunits act as molecular tethers of intracellular organelles exploited during viral entry.
  findings:
  - statement: EMC7 (with EMC4) acts as an ER-late endosome tether supporting SV40 polyomavirus delivery to the ER; EMC7's cytosolic C-terminal tail binds the late-endosomal GTPase Rab7 and EMC7/EMC4 bind the ER SNARE syntaxin-18, and EMC7 depletion blocks SV40 infection.
    reference_section_type: RESULTS
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: PubMed-verified (Nat Commun 2020, PMID:32111841). Non-canonical EMC7-specific role in organelle tethering (ER-endosome contact) and viral entry, mediated by the cytosolic tail binding Rab7 and syntaxin-18.
- id: PMID:38517390
  title: Structural insights into human EMC and its interaction with VDAC.
  findings:
  - statement: Cryo-EM of human EMC apo and VDAC1-bound states; EMC7's transmembrane helix becomes ordered upon VDAC1 binding and contributes a substantial fraction (~one-third) of the EMC-VDAC1 interface at mitochondria-ER contact sites.
    reference_section_type: RESULTS
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: PubMed-verified (Aging (Albany NY) 2024, PMID:38517390). Structural evidence that EMC7's TMH mediates the EMC-VDAC1 interaction at ER-mitochondria contact sites; supports a conformationally plastic, interface-forming role for EMC7.
- id: file:human/EMC7/EMC7-uniprot.txt
  title: UniProt entry Q9NPA0 (EMC7_HUMAN), ER membrane protein complex subunit 7
  findings:
  - statement: Single-pass type I ER membrane EMC subunit with a lumenal beta-sandwich domain; non-catalytic; part of the EMC insertase.
    reference_section_type: OTHER
core_functions:
- description: Constitutive architectural subunit of the ER membrane protein complex (EMC), contributing as a complex member to the energy-independent insertion of transmembrane domains into the ER membrane.
  molecular_function:
    id: GO:0032977
    label: membrane insertase activity
  in_complex:
    id: GO:0072546
    label: EMC complex
  locations:
  - id: GO:0005789
    label: endoplasmic reticulum membrane
  supported_by:
  - reference_id: file:human/EMC7/EMC7-uniprot.txt
    supporting_text: Component of the ER membrane protein complex (EMC).
  - reference_id: PMID:29242231
    supporting_text: EMC is a transmembrane domain insertase
  directly_involved_in:
  - id: GO:0071816
    label: tail-anchored membrane protein insertion into ER membrane
  - id: GO:0045050
    label: protein insertion into ER membrane by stop-transfer membrane-anchor sequence
proposed_new_terms: []
suggested_questions:
- question: What specific structural or functional contribution does the lumenal beta-sandwich domain of EMC7 make to EMC stability or substrate handling?
- question: Are the EMC7-WLS interactions reported in interactome screens a reflection of EMC client engagement rather than a standalone binding function?
suggested_experiments:
- description: Test whether the EMC7 lumenal beta-sandwich domain binds any carbohydrate ligand in vitro to confirm or refute the InterPro-derived carbohydrate-binding annotation.
- description: Reconstitute EMC complexes lacking EMC7 to assess its contribution to complex assembly, stability, and insertion efficiency of representative tail-anchored and multipass substrates.