Existing Annotations Review

GO Term	Evidence	Action	Reason
GO:0032977 membrane insertase activity	IBA GO_REF:0000033	KEEP AS NON CORE	Summary: Phylogenetic (IBA) assignment of membrane insertase activity with the contributes_to qualifier, reflecting EMC8 participation in the EMC insertase complex rather than an intrinsic enzymatic activity of EMC8 itself. Reason: Correct use of contributes_to for a non-catalytic subunit of the EMC insertase. EMC8 is a cytosolic accessory subunit and is not the catalytic insertase (the insertion vestibule is formed by EMC3/EMC6), so this complex-level MF is retained but not as the standalone core function. The core descriptor for EMC8 is EMC complex membership plus ER membrane localization. Supporting Evidence: file:human/EMC8/EMC8-uniprot.txt enables the energy-independent insertion into endoplasmic
GO:0045050 protein insertion into ER membrane by stop-transfer membrane-anchor sequence	IBA GO_REF:0000033	ACCEPT	Summary: Phylogenetic assignment of the EMC role in cotranslational insertion of multipass membrane proteins via stop-transfer/membrane-anchor sequences; a process EMC8 participates in as part of the complex. Reason: Consistent with the experimentally supported EMC function; the complex mediates cotranslational insertion of multipass proteins in which stop-transfer anchors become membrane-spanning helices. This is a complex-level process EMC8 is involved in. Supporting Evidence: file:human/EMC8/EMC8-uniprot.txt cotranslational insertion of multi-pass membrane proteins in which
GO:0071816 tail-anchored membrane protein insertion into ER membrane	IBA GO_REF:0000033	ACCEPT	Summary: Phylogenetic assignment of the EMC role in post-translational insertion of tail-anchored proteins; EMC8 participates as part of the complex. Reason: Consistent with experimental evidence that EMC is required for post-translational insertion of tail-anchored proteins into the ER membrane. Supporting Evidence: file:human/EMC8/EMC8-uniprot.txt post-translational insertion of tail-anchored/TA proteins in
GO:0072546 EMC complex	IBA GO_REF:0000033	ACCEPT	Summary: Phylogenetic assignment of EMC complex membership, the defining and core cellular-component association for EMC8. Reason: Core localization/membership for EMC8; directly demonstrated experimentally (IDA PMID:22119785; IPI PMID:32439656) and conserved across the EMC8/EMC9 family. Supporting Evidence: file:human/EMC8/EMC8-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 localization from the UniProt subcellular location, consistent with EMC8 being a peripheral, cytoplasmic-side subunit of the ER-resident EMC. Reason: Correct core compartment; EMC8 is a peripheral membrane protein at the ER membrane. Redundant with EXP/NAS ER membrane annotations. Supporting Evidence: file:human/EMC8/EMC8-uniprot.txt SUBCELLULAR LOCATION: Endoplasmic reticulum membrane
GO:0072546 EMC complex	IEA GO_REF:0000002	ACCEPT	Summary: InterPro-based (IPR005366, EMC8/9 family) electronic assignment to the EMC complex, consistent with the experimental membership annotation. Reason: Correct core membership; redundant with IDA/IPI/IBA evidence for EMC complex membership. Supporting Evidence: file:human/EMC8/EMC8-uniprot.txt Component of the ER membrane protein complex (EMC)
GO:0005515 protein binding	IPI PMID:16189514 Towards a proteome-scale map of the human protein-protein in...	KEEP AS NON CORE	Summary: High-throughput yeast two-hybrid human interactome capturing the EMC8-EMC2 interaction (WITH/FROM UniProtKB:Q15006). Bare protein binding is uninformative, though the EMC2 partner is the scaffold EMC8 docks onto within the complex. Reason: Records a real interaction with EMC2 (the EMC scaffold) but bare protein binding does not convey function; per guidelines not elevated to core. The functional content is captured by EMC complex membership. Supporting Evidence: file:human/EMC8/EMC8-uniprot.txt O43402; Q15006: EMC2; NbExp=17
GO:0005515 protein binding	IPI PMID:22119785 Defining human ERAD networks through an integrative mapping ...	KEEP AS NON CORE	Summary: EMC8-EMC2 interaction (WITH/FROM UniProtKB:Q15006) from the integrative ERAD/EMC mapping study that originally placed EMC8 (as COX4NB) in the mammalian EMC. Bare protein binding is uninformative. Reason: Real, biologically meaningful interaction with the EMC2 scaffold, but the bare MF term is uninformative; the membership is better captured by GO:0072546. Supporting Evidence: file:human/EMC8/EMC8-uniprot.txt O43402; Q15006: EMC2; NbExp=17
GO:0005515 protein binding	IPI PMID:26496610 A human interactome in three quantitative dimensions organiz...	KEEP AS NON CORE	Summary: EMC8-EMC2 interaction (WITH/FROM UniProtKB:Q15006) from a quantitative stoichiometry-resolved interactome. Bare protein binding is uninformative. Reason: Genuine EMC2 interaction from a high-throughput study, but bare protein binding is uninformative; intra-EMC contact captured by complex membership. Supporting Evidence: file:human/EMC8/EMC8-uniprot.txt O43402; Q15006: EMC2; NbExp=17
GO:0005515 protein binding	IPI PMID:28514442 Architecture of the human interactome defines protein commun...	KEEP AS NON CORE	Summary: EMC8-EMC2 interaction (WITH/FROM UniProtKB:Q15006) from the BioPlex interactome/community analysis. Bare protein binding is uninformative. Reason: Real EMC2 interaction from a high-throughput AP-MS network, but bare protein binding is uninformative; not elevated to core. Supporting Evidence: file:human/EMC8/EMC8-uniprot.txt O43402; Q15006: EMC2; NbExp=17
GO:0005515 protein binding	IPI PMID:30021884 Histone Interaction Landscapes Visualized by Crosslinking Ma...	KEEP AS NON CORE	Summary: EMC8-EMC2 interaction (WITH/FROM UniProtKB:Q15006) entered into IntAct from a crosslinking-MS study. The paper title concerns histone interaction landscapes, an unexpected source, but the curated datapoint records an EMC8-EMC2 contact. Reason: Curator-entered experimental IPI to the known EMC2 partner; per guidelines an experimental IPI is not removed merely because the abstract foregrounds a different topic. Bare protein binding remains uninformative, so kept as non-core. Supporting Evidence: file:human/EMC8/EMC8-uniprot.txt O43402; Q15006: EMC2; NbExp=17
GO:0005515 protein binding	IPI PMID:32296183 A reference map of the human binary protein interactome.	KEEP AS NON CORE	Summary: EMC8-EMC2 interaction (WITH/FROM UniProtKB:Q15006) from the HuRI reference binary interactome. Bare protein binding is uninformative. Reason: Genuine binary EMC2 interaction, but bare protein binding is uninformative; complex membership captures the functional content. Supporting Evidence: file:human/EMC8/EMC8-uniprot.txt O43402; Q15006: EMC2; NbExp=17
GO:0005515 protein binding	IPI PMID:32439656 Structural basis for membrane insertion by the human ER memb...	KEEP AS NON CORE	Summary: EMC8-EMC2 interaction (WITH/FROM UniProtKB:Q15006) consistent with the cryo-EM structure of the human EMC, which resolves EMC8 contacting the EMC2 scaffold. Bare protein binding is uninformative. Reason: Structurally corroborated EMC2 interaction, but bare protein binding is uninformative; the structural membership is captured by GO:0072546 EMC complex. Supporting Evidence: file:human/EMC8/EMC8-uniprot.txt O43402; Q15006: EMC2; NbExp=17
GO:0005515 protein binding	IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling...	KEEP AS NON CORE	Summary: EMC8-EMC2 interaction (WITH/FROM UniProtKB:Q15006) from BioPlex 3 dual proteome-scale networks. Bare protein binding is uninformative. Reason: Real EMC2 interaction from a large AP-MS network, but bare protein binding is uninformative; not elevated to core. Supporting Evidence: file:human/EMC8/EMC8-uniprot.txt O43402; Q15006: EMC2; NbExp=17
GO:0005515 protein binding	IPI PMID:35271311 OpenCell: Endogenous tagging for the cartography of human ce...	KEEP AS NON CORE	Summary: EMC8-EMC2 interaction (WITH/FROM UniProtKB:Q15006) from OpenCell endogenous-tagging interactome/localization. Bare protein binding is uninformative. Reason: Genuine endogenous EMC2 interaction, but bare protein binding is uninformative; the functional content is captured by EMC complex membership. Supporting Evidence: file:human/EMC8/EMC8-uniprot.txt O43402; Q15006: EMC2; NbExp=17
GO:0005783 endoplasmic reticulum	IDA GO_REF:0000052	ACCEPT	Summary: Direct immunofluorescence (HPA) evidence for ER localization, consistent with EMC8 being a subunit of the ER-resident EMC. Reason: Correct compartment; the more specific ER membrane (GO:0005789) better captures the peripheral, cytoplasmic-side association of EMC8. Supporting Evidence: file:human/EMC8/EMC8-uniprot.txt SUBCELLULAR LOCATION: Endoplasmic reticulum membrane
GO:0005789 endoplasmic reticulum membrane	NAS PMID:29242231 The ER membrane protein complex is a transmembrane domain in...	ACCEPT	Summary: ComplexPortal (NAS) assertion of EMC8 ER membrane localization, drawn from the EMC insertase characterization. Core compartment for EMC8. Reason: Correct core compartment; EMC8 is a peripheral membrane protein on the cytoplasmic side of the ER membrane. Consistent with EXP/IEA ER membrane annotations. Supporting Evidence: file:human/EMC8/EMC8-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: ComplexPortal IDA for the EMC role in cotranslational insertion of multipass proteins via stop-transfer anchors; EMC8 participates as part of the complex. Reason: Consistent with experimentally demonstrated EMC insertase function; a complex-level process EMC8 is involved in. Supporting Evidence: file:human/EMC8/EMC8-uniprot.txt cotranslational insertion of multi-pass membrane proteins in which
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: ComplexPortal IDA for the EMC role in post-translational insertion of tail-anchored proteins, the function for which Guna et al. demonstrated EMC is necessary and sufficient. EMC8 participates as part of the complex. Reason: Directly supported by the reconstitution evidence that EMC inserts tail-anchored substrates; a complex-level process EMC8 is involved in. Supporting Evidence: file:human/EMC8/EMC8-uniprot.txt post-translational insertion of tail-anchored/TA proteins in
GO:0072546 EMC complex	IPI PMID:32439656 Structural basis for membrane insertion by the human ER memb...	ACCEPT	Summary: ComplexPortal IPI placing EMC8 in the EMC, corroborated by the cryo-EM structure of the human nine-subunit complex. Core membership. Reason: Core, structurally demonstrated EMC complex membership; EMC8 (chain H) is resolved in the human EMC structures. Supporting Evidence: file:human/EMC8/EMC8-uniprot.txt ComplexPortal; CPX-5848; Endoplasmic reticulum membrane complex, EMC8 variant.
GO:0005789 endoplasmic reticulum membrane	EXP PMID:22119785 Defining human ERAD networks through an integrative mapping ...	ACCEPT	Summary: Experimental localization of EMC8 (identified as COX4NB) to the ER membrane in the integrative ERAD/EMC mapping study. Core compartment. Reason: Core compartment supported by direct experimental evidence; EMC8 associates peripherally with the ER membrane as part of EMC. Supporting Evidence: PMID:22119785 we identified 5 additional HCIPs (TTC35, TMEM32/MMGT1, TMEM85, C15orf24 and COX4NB)
GO:0032977 membrane insertase activity	IMP PMID:29809151 The ER membrane protein complex interacts cotranslationally ...	KEEP AS NON CORE	Summary: IMP (loss-of-function) evidence that EMC subunits contribute to the membrane insertase activity of the complex, assigned to EMC8 with the contributes_to qualifier. The full text (subunit perturbation in cotranslational multipass biogenesis) was read by the curator. Reason: Appropriate contributes_to assignment for a non-catalytic accessory subunit of the EMC insertase. EMC8 is not itself catalytic (the EMC3/EMC6 vestibule performs insertion), so this complex-level MF is retained but not as the standalone core function. Not removed, since contributes_to is the intended qualifier for subunit contributions to a complex activity. Supporting Evidence: file:human/EMC8/EMC8-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 (EMC knockout/depletion in GPCR topogenesis) that the EMC has membrane insertase activity, assigned to EMC8 with contributes_to. Full text read by the curator. Reason: Correct contributes_to assignment for a non-catalytic accessory subunit; the catalytic insertase activity is a property of the complex, not of EMC8 alone. Kept but not core for the individual subunit. Supporting Evidence: file:human/EMC8/EMC8-uniprot.txt the topology of multi-pass
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: IMP evidence that EMC (including EMC8) is required for cotranslational insertion of multipass membrane proteins via stop-transfer anchors. Reason: Consistent with the experimentally supported EMC function; loss of EMC subunits impairs cotranslational multipass insertion. A complex-level process EMC8 is involved in. Supporting Evidence: file:human/EMC8/EMC8-uniprot.txt cotranslational insertion of multi-pass membrane proteins in which
GO:0045050 protein insertion into ER membrane by stop-transfer membrane-anchor sequence	IMP PMID:30415835 EMC Is Required to Initiate Accurate Membrane Protein Topoge...	ACCEPT	Summary: IMP evidence (EMC knockout impairs accurate GPCR/multipass topogenesis) supporting the EMC role in cotranslational insertion via stop-transfer anchors; EMC8 participates as part of the complex. Reason: Consistent with experimental topogenesis evidence; EMC mediates cotranslational insertion that sets multipass topology. A complex-level process EMC8 is involved in. Supporting Evidence: file:human/EMC8/EMC8-uniprot.txt the proper cotranslational insertion of N-terminal
GO:0016020 membrane	HDA PMID:19946888 Defining the membrane proteome of NK cells.	KEEP AS NON CORE	Summary: High-throughput membrane-proteome (NK-cell) MS dataset assigning generic membrane localization. Correct but a generic parent of the ER membrane localization. Reason: Accurate but low-information; the specific ER membrane (GO:0005789) better captures the localization of EMC8. Supporting Evidence: file:human/EMC8/EMC8-uniprot.txt SUBCELLULAR LOCATION: Endoplasmic reticulum membrane
GO:0005737 cytoplasm	IDA PMID:22119785 Defining human ERAD networks through an integrative mapping ...	KEEP AS NON CORE	Summary: Direct evidence consistent with EMC8 being on the cytoplasmic side of the ER membrane; cytoplasm is a correct but less specific compartment than ER membrane. Reason: Correct (EMC8 is a peripheral, cytoplasmic-side subunit) but generic; the ER membrane localization and EMC complex membership are the informative core terms. Supporting Evidence: file:human/EMC8/EMC8-uniprot.txt Cytoplasmic side
GO:0072546 EMC complex	IDA PMID:22119785 Defining human ERAD networks through an integrative mapping ...	ACCEPT	Summary: Direct experimental identification of EMC8 (as COX4NB) as a component of the mammalian EMC; the foundational evidence for the core complex membership of EMC8. Reason: Core, directly demonstrated EMC complex membership; this is the defining cellular-component association for EMC8. Supporting Evidence: PMID:22119785 we identified 5 additional HCIPs (TTC35, TMEM32/MMGT1, TMEM85, C15orf24 and COX4NB)

Core Functions

Cytosolic, non-catalytic accessory subunit of the ER membrane protein complex (EMC); its core role is to be a constitutive component of the EMC, an ER transmembrane-domain insertase/chaperone, docking onto the EMC2 scaffold on the cytoplasmic side of the ER membrane and providing a cytosolic client-docking surface (e.g., the EMC8 "Cyto dock" for CaVbeta3) during membrane-protein assembly.

Cellular Locations:

endoplasmic reticulum membrane

In Complex:

EMC complex

Supporting Evidence:

file:human/EMC8/EMC8-uniprot.txt
Component of the ER membrane protein complex (EMC)
PMID:22119785
we identified 5 additional HCIPs (TTC35, TMEM32/MMGT1, TMEM85, C15orf24 and COX4NB)

As part of the EMC, contributes to membrane insertase activity, participating in energy-independent insertion of newly synthesized membrane proteins into the ER membrane (cotranslational multipass insertion via stop-transfer anchors and post-translational tail-anchored protein insertion). EMC8 is not itself catalytic; the insertion vestibule is provided by EMC3/EMC6.

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

Supporting Evidence:

file:human/EMC8/EMC8-uniprot.txt
enables the energy-independent insertion into endoplasmic

References

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

GO_REF:0000052

Gene Ontology annotation based on curation of immunofluorescence data

PMID:16189514

Towards a proteome-scale map of the human protein-protein interaction network.

PMID:19946888

Defining the membrane proteome of NK cells.

PMID:22119785

Defining human ERAD networks through an integrative mapping strategy.

Identified EMC8 (as COX4NB) as a high-confidence component of the mammalian ER membrane protein complex (mEMC), establishing EMC complex membership and ER membrane/cytoplasm localization.

PMID:26496610

A human interactome in three quantitative dimensions organized by stoichiometries and abundances.

PMID:28514442

Architecture of the human interactome defines protein communities and disease networks.

PMID:29242231

The ER membrane protein complex is a transmembrane domain insertase.

The EMC is a transmembrane-domain insertase that catalyzes insertion of tail-anchored and other substrates into the ER membrane in a reconstituted system; EMC8 is a subunit of this complex.

PMID:29809151

The ER membrane protein complex interacts cotranslationally to enable biogenesis of multipass membrane proteins.

EMC engages ribosomes cotranslationally and is required for biogenesis of multipass membrane proteins; depletion of EMC subunits impairs insertion.

PMID:30021884

Histone Interaction Landscapes Visualized by Crosslinking Mass Spectrometry in Intact Cell Nuclei.

PMID:30415835

EMC Is Required to Initiate Accurate Membrane Protein Topogenesis.

EMC mediates cotranslational insertion of the first TMD of GPCRs and other multipass proteins and cooperates with Sec61 to ensure accurate topogenesis; EMC knockout impairs correct topology.

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 nine-subunit EMC; substrate insertion occurs via an enclosed hydrophilic vestibule formed by EMC3 and EMC6, with EMC8 resolved as a cytosolic-facing subunit.

PMID:33961781

Dual proteome-scale networks reveal cell-specific remodeling of the human interactome.

PMID:35271311

OpenCell: Endogenous tagging for the cartography of human cellular organization.

PMID:37196677

EMC chaperone-Ca(V) structure reveals an ion channel assembly intermediate.

Cryo-EM of human EMC bound to a CaV1.2-CaVbeta3 assembly intermediate; EMC8 forms a specific cytosolic client-docking interface ("Cyto dock"/"EMC8 site", ~962 A^2 centered on the last helix of EMC8) with CaVbeta3, binding two CaVbeta loops and ordering an otherwise disordered CaVbeta region, demonstrating an EMC8-specific chaperone/assembly role beyond generic insertion.

PMID:32459176

The architecture of EMC reveals a path for membrane protein insertion.

EMC2 forms an alpha-solenoid that clamps around EMC8 in the cytosolic basket; EMC8 is a ~23 kDa monomer ~44% identical to EMC9, and EMC8 and EMC9 are mutually exclusive subunits (no ternary EMC2-EMC8-EMC9 complex forms), supporting EMC8 as a structural assembly/scaffold subunit of the cytosolic module.

PMID:35287476

The Function, Structure, and Origins of the ER Membrane Protein Complex.

Authoritative review of EMC function, structure, and evolution; places EMC2, EMC8, and EMC9 as the cytosolic subunits and EMC8/EMC9 as mutually exclusive paralogs of the cytosolic cradle that engages membrane-protein clients before insertion.

PMID:38517390

Structural insights into human EMC and its interaction with VDAC.

Cryo-EM of human EMC apo and VDAC1-bound states at mitochondria-ER contact sites, with a hydrophilic-vestibule "gating plug" conformational change proposed to regulate EMC function; EMC8 is a cytosolic subunit of the complexes studied (no EMC8-specific mechanistic role assigned in this study).

file:human/EMC8/EMC8-uniprot.txt

UniProt entry O43402 (EMC8_HUMAN), ER membrane protein complex subunit 8

EMC8 is a cytosolic, peripheral subunit (cytoplasmic side) of the ER membrane protein complex (EMC), an energy-independent TMD insertase for newly synthesized membrane proteins; mediates cotranslational multipass and post-translational tail-anchored insertion. EMC8 and EMC9 are mutually exclusive subunits; EMC8 belongs to the EMC8/EMC9 family and contains an MPN domain.

Suggested Experiments

Experiment: Compare substrate-insertion profiles (e.g., ribosome profiling / proteomics of membrane-protein biogenesis) in EMC8-knockout versus EMC9-knockout versus EMC8/EMC9 double-knockout cells to define paralog-specific contributions to EMC function.

Experiment: Reconstitute EMC insertase activity in liposomes with and without EMC8 (and with EMC9 substituted) to test whether EMC8 is required for complex assembly, stability, or insertion efficiency of defined substrates.

Experiment: Use cryo-EM and crosslinking-MS to map the EMC8-EMC2 interface and determine how EMC8 incorporation affects the architecture of the cytosolic cap of the EMC.

Deep Research

Falcon

(EMC8-deep-research-falcon.md)

this with annotations you find in gene/protein databases, but these can be outdated or inaccurate. Falcon Edison Scientific Literature 21 citations 2 artifacts 2026-06-12T01:52:47.754699

Edison artifact artifact-00 (text/markdown)

## Context ID: pqac-00000011 The requested figures and panels showing the interaction between the EMC8 site / Cyto dock and CaVβ3 are extracted from Figure 1 an (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.

Comprehensive Research Report: Human EMC8 (UniProt O43402)—Functional Annotation

1) Identity verification (critical disambiguation)

Target verified: The evidence assembled here concerns human EMC8, annotated as ER membrane protein complex subunit 8, a soluble/cytosolic subunit of the ER membrane protein complex (EMC), and a paralog of EMC9 in mammals. Multiple primary studies explicitly place EMC8 among the cytosolic EMC subunits (with EMC2 and EMC9), consistent with the UniProt-provided identity (O43402; alt names include FAM158B/COX4NB). (tian2019proteomicanalysisidentifies pages 1-3, odonnell2020thearchitectureof pages 2-4)

2) Key concepts and definitions (current understanding)

2.1 The ER membrane protein complex (EMC)

The endoplasmic reticulum (ER) is the major site for membrane protein insertion, folding, and assembly. Many membrane proteins require dedicated insertases and membrane chaperones to reduce the energetic cost of inserting transmembrane domains (TMDs) and to stabilize partially assembled helices/complexes. A core conceptual distinction is between SecY/Sec61-family systems (full aqueous channel suited for longer translocation) and Oxa1/YidC-like insertases that provide a partial, hydrophilic vestibule that accommodates shorter segments/loops adjacent to TMDs and supports lateral release into the membrane. (Hegde 2022; publication date June 2022; URL https://doi.org/10.1146/annurev-biochem-032620-104553) (hegde2022thefunctionstructure pages 2-4)

In this framework, EMC is an abundant, conserved multi-subunit ER factor implicated in TMD insertion and also in later steps of membrane protein folding/assembly. (Hegde 2022; URL above) (hegde2022thefunctionstructure pages 4-6)

2.2 EMC8: definition and placement within EMC

Across studies of mammalian EMC, EMC8 is a cytosolic subunit (not membrane-spanning) and is closely related to EMC9. In mammals, EMC8 and EMC9 are described as partially redundant/paralogous, and EMC8 is ~23 kDa with ~44% identity to EMC9. (O’Donnell et al., May 2020; URL https://doi.org/10.7554/eLife.57887) (odonnell2020thearchitectureof pages 2-4, odonnell2020thearchitectureof pages 1-2)

3) Molecular function of EMC8 within EMC: structure-informed mechanism

3.1 Structural role: EMC8 as part of the cytosolic cap/vestibule and assembly scaffold

Human EMC architecture reveals a cytosolic vestibule/cap that binds client TMDs and connects to an intramembrane path for insertion. In a detailed biochemical/cryo-EM architecture study, the EMC cytosolic region forms a “large, moderately hydrophobic vestibule” that can bind substrate TMDs and leads into a lumenally sealed, lipid-exposed intramembrane groove that can accommodate a single TMD; this provides a plausible pathway for energy-independent membrane insertion consistent with EMC lacking nucleotide-binding domains. (O’Donnell et al., May 2020; URL https://doi.org/10.7554/eLife.57887) (odonnell2020thearchitectureof pages 1-2)

Within the human EMC cytosolic basket, EMC8 is positioned at the cytosolic face as part of the structural scaffold: EMC2 forms an α-solenoid that clamps around EMC8, and EMC8 participates in a composite interface with other cytosolic features of the complex. Structure-guided mutational perturbations at interfaces involving EMC8 can disrupt subunit binding in vitro, supporting that EMC8 contributes to complex assembly/stability needed for EMC activity. (Pleiner et al., July 2020; URL https://doi.org/10.1126/science.abb5008) (pleiner2020structuralbasisfor pages 1-3)

3.2 Functional mapping: EMC8-proximal regions influence client-specific outcomes

Structure-function analysis across EMC client classes indicates that features near the cytosolic cap (including regions adjacent to EMC8/9) modulate client stability (e.g., increasing SQS levels when altered), supporting that the cytosolic cap is functionally coupled to insertase/chaperone outcomes. (Miller-Vedam et al., Sep 2020; URL https://doi.org/10.1101/2020.09.02.280008) (millervedam2020structuralandmechanistic pages 25-28)

4) Subcellular localization and topology

Across mammalian EMC studies, EMC8 is described as cytosolic/soluble, consistent with localization on the cytosolic face of the ER membrane as part of the EMC cytosolic domain. (Tian et al., Sep 2019; URL https://doi.org/10.1016/j.celrep.2019.08.006) (tian2019proteomicanalysisidentifies pages 1-3)

5) Experimental evidence linking EMC8/EMC to client insertion and chaperoning

5.1 Broad client spectrum: proteomics-defined EMC dependency and TMD features

A quantitative proteomics analysis identified 36 EMC-dependent versus 171 EMC-independent membrane proteins. This work supported a mechanistic model in which EMC promotes biogenesis/integration especially for TMDs containing polar/charged residues, and it showed that TMD mutagenesis can convert proteins between EMC-dependent and independent categories, indicating that TMD physicochemical features can drive EMC reliance. (Tian et al., Sep 2019; URL https://doi.org/10.1016/j.celrep.2019.08.006) (tian2019proteomicanalysisidentifies pages 1-3)

Although this proteomics evidence is primarily about EMC as a complex, it is relevant to EMC8 because EMC8 is one of the soluble subunits required for intact EMC assembly and therefore for these client outcomes. (tian2019proteomicanalysisidentifies pages 1-3, pleiner2020structuralbasisfor pages 1-3)

5.2 2023–2024 high-impact developments: EMC8 in a client-bound assembly intermediate (CaV channels)

A major advance was the client-bound cryo-EM structure of an EMC chaperone complex with a high-voltage activated calcium channel assembly intermediate. In this structure, EMC8 contributes directly to a cytosolic docking interface (“Cyto dock”) with CaVβ3, demonstrating a specific assembly/chaperone role beyond generic insertase concepts. (Chen et al., May 2023; URL https://doi.org/10.1038/s41586-023-06175-5) (chen2023emcchaperone–cavstructure pages 3-4)

Key quantitative structural findings include:
- The Cyto dock interface is ~1,500 Å² total. (chen2023emcchaperone–cavstructure pages 3-4)
- The EMC8-centered subsite (“EMC8 site”) is 962 Å², centered on the last helix of EMC8. (chen2023emcchaperone–cavstructure pages 3-4)
- Two CaVβ loops bind the EMC8 site: β7–α4 (Thr218–Ala243) and β8–β9 (Pro277–Lys282), forming hydrogen-bond and salt-bridge networks involving seven conserved CaVβ residues. (chen2023emcchaperone–cavstructure pages 3-4)
- A CaVβ region (Lys225–Ser245) that is disordered in isolated CaVβ becomes ordered upon EMC8 binding, implying EMC8-mediated stabilization of an assembly intermediate. (chen2023emcchaperone–cavstructure pages 3-4)

Visual evidence: The retrieved figure panels illustrate the Cyto dock and EMC8-site interaction geometry and contact details. (chen2023emcchaperone–cavstructure media 6624cdd7, chen2023emcchaperone–cavstructure media f7eece75, chen2023emcchaperone–cavstructure media b43f9754, chen2023emcchaperone–cavstructure media 579bfd7d)

5.3 2024 structural development: EMC interaction with VDAC at ER–mitochondria contacts

A 2024 cryo-EM study reported apo and VDAC1-bound human EMC structures at 3.47 Å and 3.32 Å, respectively, and described a specific interaction with VDAC proteins at mitochondria–ER contact sites. The study proposed that a “gating plug” inside the EMC hydrophilic vestibule changes conformation upon VDAC binding and may regulate EMC functional modes (including an insertase vs alternative state). The provided evidence does not resolve an EMC8-specific mechanistic assignment within this interaction, but it adds to 2023–2024 views that EMC has multiple regulated functional states. (Li et al., Mar 2024; URL https://doi.org/10.18632/aging.205660) (OpenTargets Search: -EMC8)

6) Disease/phenotype associations and expert analysis (authoritative sources)

6.1 Expert consensus: why EMC perturbation can be pleiotropic

Authoritative review synthesis emphasizes that EMC supports insertion/biogenesis of multi-pass membrane proteins and that validated EMC-dependent client lists remain relatively limited compared with the breadth of reported phenotypes; this is consistent with EMC acting at a fundamental and failure-prone step in membrane protein biogenesis, where disruption can yield broad downstream effects. (Hegde 2022; URL https://doi.org/10.1146/annurev-biochem-032620-104553) (hegde2022thefunctionstructure pages 19-20)

6.2 EMC8-specific human disease genetics: limited direct evidence in retrieved sources

Within the retrieved evidence set, direct, mechanistically validated human Mendelian disease links for EMC8 were not available. However, Open Targets reports low-scoring disease associations for EMC8 (ENSG00000131148), including exfoliation syndrome, jaw disease, diverticular disease, retinitis pigmentosa with erythrocytic microcytosis, and familial ocular anterior segment mesenchymal dysgenesis, each supported by a small number of evidence entries in the platform output (without literature identifiers in the retrieved snippet). (Open Targets; retrieved context) (OpenTargets Search: -EMC8)

Interpretation: These Open Targets associations should be treated as hypothesis-generating rather than definitive, because the retrieved evidence does not include study-level details (e.g., variant pathogenicity, functional validation). (OpenTargets Search: -EMC8)

7) Current applications and real-world implementations

Ion channel biogenesis and drug-relevant assembly control: The 2023 client-bound structure provides a direct mechanistic basis for how EMC (via EMC8 at the Cyto dock) can act as a chaperone/holdase-like factor for CaV channel assembly, which is directly relevant to excitable-tissue physiology and drug-target biology (CaV channels are major pharmacological targets). (Chen et al., May 2023; https://doi.org/10.1038/s41586-023-06175-5) (chen2023emcchaperone–cavstructure pages 3-4)
Membrane-protein engineering and expression: The proteomic observation that TMD sequence features influence EMC dependence suggests practical strategies for engineering membrane proteins for improved biogenesis (e.g., tuning marginal hydrophobicity/polar content of problematic helices), though these are not yet formalized as a standardized toolkit in the retrieved sources. (Tian et al., Sep 2019; https://doi.org/10.1016/j.celrep.2019.08.006) (tian2019proteomicanalysisidentifies pages 1-3)
Organelle contact site biology: The proposed VDAC–EMC interaction at ER–mitochondria contacts suggests EMC may be leveraged as a structural/functional probe for contact-site regulation in aging-related or metabolic contexts, though direct EMC8-specific translational strategies are not yet established in the retrieved evidence. (Li et al., Mar 2024; https://doi.org/10.18632/aging.205660) (OpenTargets Search: -EMC8)

8) Key statistics and data (from recent and foundational studies)

Client spectrum (proteomics): 36 EMC-dependent vs 171 EMC-independent membrane proteins identified in a quantitative proteomics framework. (Tian et al., Sep 2019; https://doi.org/10.1016/j.celrep.2019.08.006) (tian2019proteomicanalysisidentifies pages 1-3)
Client-bound assembly interface metrics: CaV–EMC Cyto dock ~1,500 Å²; EMC8 site 962 Å²; EMC2 site ~550 Å²; defined residue ranges for CaVβ3 loops contacting EMC8. (Chen et al., May 2023; https://doi.org/10.1038/s41586-023-06175-5) (chen2023emcchaperone–cavstructure pages 3-4)
Structural resolution benchmarks: Human EMC apo and VDAC1-bound structures at 3.47 Å and 3.32 Å. (Li et al., Mar 2024; https://doi.org/10.18632/aging.205660) (OpenTargets Search: -EMC8)
Disease association scores (database-level): Open Targets association scores for several diseases are in the ~0.035–0.076 range in the retrieved output. (OpenTargets Search: -EMC8)

9) Summary: best-supported functional annotation for EMC8

Primary supported role: EMC8 is a cytosolic structural and client-interaction subunit of the ER membrane protein complex. Evidence supports EMC8 as part of the cytosolic cap/vestibule essential for EMC assembly and for the EMC’s ability to engage substrates during membrane protein insertion and assembly. (pleiner2020structuralbasisfor pages 1-3, odonnell2020thearchitectureof pages 1-2)

Most direct EMC8-specific mechanistic evidence (2023–2024): EMC8 provides a defined client-binding surface for CaVβ3 in an EMC–CaV assembly intermediate, consistent with a chaperone/assembly function in addition to insertase activity attributed to the overall complex. (chen2023emcchaperone–cavstructure pages 3-4, chen2023emcchaperone–cavstructure media 6624cdd7, chen2023emcchaperone–cavstructure media f7eece75, chen2023emcchaperone–cavstructure media b43f9754, chen2023emcchaperone–cavstructure media 579bfd7d)

Evidence gaps (transparent limitations): Direct EMC8-specific human disease mechanisms and a curated list of EMC8-specific clients (distinct from general EMC dependence) remain limited in the retrieved literature set; Open Targets provides low-score associations without study-level detail in the snippet. (OpenTargets Search: -EMC8, hegde2022thefunctionstructure pages 19-20)

Evidence summary table

Claim/insight about EMC8	Evidence type	Key quantitative details	System/clients studied	Citation
EMC8 is a cytosolic subunit of the human ER membrane protein complex and is functionally redundant with EMC9 in mammals.	Cryo-EM/biochemical architecture	EMC8 is ~23 kDa and ~44% identical to EMC9; no free EMC subunits detected, indicating stable complex assembly.	Human EMC; general membrane protein biogenesis	O'Donnell et al., 2020, eLife, https://doi.org/10.7554/eLife.57887 (odonnell2020thearchitectureof pages 2-4, odonnell2020thearchitectureof pages 1-2)
EMC8 helps form the cytosolic vestibule/cap that engages substrate transmembrane domains during EMC-mediated insertion.	Cryo-EM/biochemical mechanism	EMC has a “large, moderately hydrophobic vestibule” leading to a lumenally sealed, lipid-exposed intramembrane groove; insertase reaction described as energy independent.	Human EMC; tail-anchored client SQS and terminal TMD substrates	O'Donnell et al., 2020, eLife, https://doi.org/10.7554/eLife.57887 (odonnell2020thearchitectureof pages 2-4, odonnell2020thearchitectureof pages 1-2)
EMC8 is a structural assembly factor in the human EMC cytosolic basket, binding EMC2 and contributing to complex stability.	Cryo-EM/structure-guided mutagenesis	Human EMC resolved at 3.4 Å; EMC2 clamps around EMC8 via an extensive hydrophobic surface, and mutations at EMC8/EMC2/EMC3/EMC5 interfaces disrupted subunit binding in vitro.	Human EMC reconstituted in lipid nanodiscs	Pleiner et al., 2020, Science, https://doi.org/10.1126/science.abb5008 (pleiner2020structuralbasisfor pages 1-3)
In mammals, EMC8 is one of the soluble/cytosolic EMC components rather than a membrane-spanning subunit.	Quantitative proteomics/background functional study	Mammalian EMC described with 10 subunits; EMC2, EMC8, and EMC9 are cytosolic; Tian et al. defined 36 EMC-dependent versus 171 EMC-independent membrane proteins.	Mammalian EMC; broad membrane protein client sets	Tian et al., 2019, Cell Reports, https://doi.org/10.1016/j.celrep.2019.08.006 (tian2019proteomicanalysisidentifies pages 1-3)
EMC dependency is linked to difficult transmembrane segments containing polar/charged residues, supporting an EMC8-containing cytosolic recognition/chaperoning role in the intact complex.	Proteomics/mutagenesis	36 EMC-dependent and 171 EMC-independent membrane proteins identified; TMD mutagenesis could convert EMC dependency.	Diverse membrane proteins; disease-relevant examples include CFTR and connexin-32 at EMC-complex level	Tian et al., 2019, Cell Reports, https://doi.org/10.1016/j.celrep.2019.08.006 (tian2019proteomicanalysisidentifies pages 1-3)
Reviews place EMC8 within the cytosolic subcomplex of EMC and interpret EMC as both an insertase and membrane-protein biogenesis factor/chaperone.	Authoritative review	EMC is considered a nine-protein complex in many species with EMC8/EMC9 as mutually exclusive paralogs; validated EMC-dependent proteins remain limited to roughly ~a dozen in the literature summarized.	EMC broadly; multipass membrane proteins and cotranslational biogenesis	Hegde, 2022, Annual Review of Biochemistry, https://doi.org/10.1146/annurev-biochem-032620-104553 (hegde2022thefunctionstructure pages 19-20, hegde2022thefunctionstructure pages 4-6, hegde2022thefunctionstructure pages 2-4)
Structure-function mapping places EMC8 near the cytoplasmic cap adjacent to EMC3, a region that influences client-specific biogenesis.	Cryo-EM/functional mutagenesis	Mutating the cytoplasmic cap near EMC8/9 increased SQS levels; distinct EMC regions separately affected tail-anchored, N-terminal, and polytopic clients.	SQS, B1AR, TMEM97	Miller-Vedam et al., 2020, eLife preprint record, https://doi.org/10.1101/2020.09.02.280008 (millervedam2020structuralandmechanistic pages 25-28)
2023 cryo-EM shows EMC8 directly contacts CaVβ3 in a client-bound EMC assembly intermediate, demonstrating a specific EMC8-dependent cytosolic docking role.	Cryo-EM/client-bound structure	Cyto dock area ~1,500 Å^2; EMC8-centered subsite 962 Å^2; adjacent EMC2 site ~550 Å^2; overall maps at 3.4 Å/3.3 Å with local 2.4–2.0 Å.	Human EMC–CaV1.2(ΔC)–CaVβ3 complex	Chen et al., 2023, Nature, https://doi.org/10.1038/s41586-023-06175-5 (chen2023emcchaperone–cavstructure pages 3-4, chen2023emcchaperone–cavstructure media 6624cdd7, chen2023emcchaperone–cavstructure media f7eece75, chen2023emcchaperone–cavstructure media b43f9754, chen2023emcchaperone–cavstructure media 579bfd7d)
EMC8 binding stabilizes otherwise disordered regions of CaVβ3, supporting a chaperone/assembly role beyond simple TMD insertion.	Cryo-EM/client interaction analysis	Two CaVβ loops (β7–α4, Thr218–Ala243; β8–β9, Pro277–Lys282) bind the EMC8 site; a CaVβ region Lys225–Ser245 becomes ordered on EMC8 binding; seven conserved CaVβ residues participate in H-bond/salt-bridge networks.	Human CaV1.2/CaVβ3 assembly intermediate	Chen et al., 2023, Nature, https://doi.org/10.1038/s41586-023-06175-5 (chen2023emcchaperone–cavstructure pages 3-4, chen2023emcchaperone–cavstructure media 6624cdd7, chen2023emcchaperone–cavstructure media f7eece75, chen2023emcchaperone–cavstructure media b43f9754, chen2023emcchaperone–cavstructure media 579bfd7d)
A 2024 structural study supports multifunctionality of human EMC and identifies a VDAC-bound state at mitochondria–ER contact sites, but the provided snippet does not assign a specific direct mechanistic role to EMC8.	Cryo-EM/structural study	Apo and VDAC1-bound human EMC structures at 3.47 Å and 3.32 Å; VDAC interaction observed at mitochondria-ER contact sites; gating-plug conformational change proposed to regulate function.	Human EMC; VDAC1	Li et al., 2024, Aging (Albany NY), https://doi.org/10.18632/aging.205660
Disease links for EMC8 specifically are currently weak/indirect in the provided evidence, with Open Targets listing only low-score associations and no literature details in the retrieved snippet.	Disease-target database association	Example association scores: jaw disease 0.07599; diverticular disease 0.03701; retinitis pigmentosa and erythrocytic microcytosis 0.03655; familial ocular anterior segment mesenchymal dysgenesis 0.03620; exfoliation syndrome 0.03484.	Human EMC8 disease associations	Open Targets platform result for EMC8 (context output) (OpenTargets Search: -EMC8)

Table: This table compiles the main structural, mechanistic, proteomic, and disease-association evidence for human EMC8 from the provided sources. It highlights where EMC8 is best supported as a cytosolic structural/chaperone component of the ER membrane protein complex and where evidence remains indirect or limited.

References

(tian2019proteomicanalysisidentifies pages 1-3): Songhai Tian, Quan Wu, Bo Zhou, Mei Yuk Choi, Bo Ding, Wei Yang, and Min Dong. Proteomic analysis identifies membrane proteins dependent on the er membrane protein complex. Cell reports, 28:2517-2526.e5, Sep 2019. URL: https://doi.org/10.1016/j.celrep.2019.08.006, doi:10.1016/j.celrep.2019.08.006. This article has 79 citations and is from a highest quality peer-reviewed journal.
(odonnell2020thearchitectureof pages 2-4): John P O'Donnell, Ben P Phillips, Yuichi Yagita, Szymon Juszkiewicz, Armin Wagner, Duccio Malinverni, Robert J Keenan, Elizabeth A Miller, and Ramanujan S Hegde. The architecture of emc reveals a path for membrane protein insertion. May 2020. URL: https://doi.org/10.7554/elife.57887, doi:10.7554/elife.57887. This article has 121 citations and is from a domain leading peer-reviewed journal.
(hegde2022thefunctionstructure pages 2-4): 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.
(hegde2022thefunctionstructure pages 4-6): 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.
(odonnell2020thearchitectureof pages 1-2): John P O'Donnell, Ben P Phillips, Yuichi Yagita, Szymon Juszkiewicz, Armin Wagner, Duccio Malinverni, Robert J Keenan, Elizabeth A Miller, and Ramanujan S Hegde. The architecture of emc reveals a path for membrane protein insertion. May 2020. URL: https://doi.org/10.7554/elife.57887, doi:10.7554/elife.57887. This article has 121 citations and is from a domain leading peer-reviewed journal.
(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.
(millervedam2020structuralandmechanistic pages 25-28): Lakshmi E. Miller-Vedam, Bastian Bräuning, Katerina D. Popova, Nicole T. Schirle Oakdale, Jessica L. Bonnar, Jesuraj Rajan Prabu, Elizabeth A. Boydston, Natalia Sevillano, Matthew J. Shurtleff, Robert M. Stroud, Charles S. Craik, Brenda A. Schulman, Adam Frost, and Jonathan S. Weissman. Structural and mechanistic basis of the emc-dependent biogenesis of distinct transmembrane clients. eLife, Sep 2020. URL: https://doi.org/10.1101/2020.09.02.280008, doi:10.1101/2020.09.02.280008. This article has 102 citations and is from a domain leading peer-reviewed journal.
(chen2023emcchaperone–cavstructure pages 3-4): Zhou Chen, Abhisek Mondal, Fayal Abderemane-Ali, Seil Jang, Sangeeta Niranjan, José L. Montaño, Balyn W. Zaro, and Daniel L. Minor. Emc chaperone–cav structure reveals an ion channel assembly intermediate. Nature, 619:410-419, May 2023. URL: https://doi.org/10.1038/s41586-023-06175-5, doi:10.1038/s41586-023-06175-5. This article has 77 citations and is from a highest quality peer-reviewed journal.
(chen2023emcchaperone–cavstructure media 6624cdd7): Zhou Chen, Abhisek Mondal, Fayal Abderemane-Ali, Seil Jang, Sangeeta Niranjan, José L. Montaño, Balyn W. Zaro, and Daniel L. Minor. Emc chaperone–cav structure reveals an ion channel assembly intermediate. Nature, 619:410-419, May 2023. URL: https://doi.org/10.1038/s41586-023-06175-5, doi:10.1038/s41586-023-06175-5. This article has 77 citations and is from a highest quality peer-reviewed journal.
(chen2023emcchaperone–cavstructure media f7eece75): Zhou Chen, Abhisek Mondal, Fayal Abderemane-Ali, Seil Jang, Sangeeta Niranjan, José L. Montaño, Balyn W. Zaro, and Daniel L. Minor. Emc chaperone–cav structure reveals an ion channel assembly intermediate. Nature, 619:410-419, May 2023. URL: https://doi.org/10.1038/s41586-023-06175-5, doi:10.1038/s41586-023-06175-5. This article has 77 citations and is from a highest quality peer-reviewed journal.
(chen2023emcchaperone–cavstructure media b43f9754): Zhou Chen, Abhisek Mondal, Fayal Abderemane-Ali, Seil Jang, Sangeeta Niranjan, José L. Montaño, Balyn W. Zaro, and Daniel L. Minor. Emc chaperone–cav structure reveals an ion channel assembly intermediate. Nature, 619:410-419, May 2023. URL: https://doi.org/10.1038/s41586-023-06175-5, doi:10.1038/s41586-023-06175-5. This article has 77 citations and is from a highest quality peer-reviewed journal.
(chen2023emcchaperone–cavstructure media 579bfd7d): Zhou Chen, Abhisek Mondal, Fayal Abderemane-Ali, Seil Jang, Sangeeta Niranjan, José L. Montaño, Balyn W. Zaro, and Daniel L. Minor. Emc chaperone–cav structure reveals an ion channel assembly intermediate. Nature, 619:410-419, May 2023. URL: https://doi.org/10.1038/s41586-023-06175-5, doi:10.1038/s41586-023-06175-5. This article has 77 citations and is from a highest quality peer-reviewed journal.
(OpenTargets Search: -EMC8): Open Targets Query (-EMC8, 5 results). Buniello, A. et al. (2025). Open Targets Platform: facilitating therapeutic hypotheses building in drug discovery. Nucleic Acids Research.
(hegde2022thefunctionstructure pages 19-20): 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.

Artifacts

Edison artifact artifact-00

Citations

hegde2022thefunctionstructure pages 2-4
hegde2022thefunctionstructure pages 4-6
odonnell2020thearchitectureof pages 1-2
pleiner2020structuralbasisfor pages 1-3
millervedam2020structuralandmechanistic pages 25-28
tian2019proteomicanalysisidentifies pages 1-3
hegde2022thefunctionstructure pages 19-20
odonnell2020thearchitectureof pages 2-4
https://doi.org/10.1146/annurev-biochem-032620-104553
https://doi.org/10.7554/eLife.57887
https://doi.org/10.1126/science.abb5008
https://doi.org/10.1101/2020.09.02.280008
https://doi.org/10.1016/j.celrep.2019.08.006
https://doi.org/10.1038/s41586-023-06175-5
https://doi.org/10.18632/aging.205660
https://doi.org/10.1016/j.celrep.2019.08.006,
https://doi.org/10.7554/elife.57887,
https://doi.org/10.1146/annurev-biochem-032620-104553,
https://doi.org/10.1126/science.abb5008,
https://doi.org/10.1101/2020.09.02.280008,
https://doi.org/10.1038/s41586-023-06175-5,

📚 Additional Documentation

Notes

(EMC8-notes.md)

EMC8 (O43402) review notes

Identity / overview

EMC8 = ER membrane protein complex subunit 8 (human, 210 aa). Synonyms: C16orf2/C16orf4, COX4AL, COX4NB, FAM158B, NOC4, "Neighbor of COX4". HGNC:7864, GeneID 10328 [file:human/EMC8/EMC8-uniprot.txt "RecName: Full=ER membrane protein complex subunit 8"], [file:human/EMC8/EMC8-uniprot.txt "AltName: Full=Neighbor of COX4"].
It is a cytosolic, peripheral subunit of the nine-subunit EMC, an ER membrane insertase/chaperone. EMC8 sits on the cytoplasmic side of the membrane and is non-catalytic [file:human/EMC8/EMC8-uniprot.txt "SUBCELLULAR LOCATION: Endoplasmic reticulum membrane"], [file:human/EMC8/EMC8-uniprot.txt "Peripheral membrane protein"], [file:human/EMC8/EMC8-uniprot.txt "Cytoplasmic side"].
Belongs to the EMC8/EMC9 family; EMC8 and EMC9 are mutually exclusive subunits of EMC [file:human/EMC8/EMC8-uniprot.txt "Belongs to the EMC8/EMC9 family."], [file:human/EMC8/EMC8-uniprot.txt "EMC8 and EMC9 are mutually exclusive subunits of the EMC complex"].
Contains a single MPN domain (residues 4-150), a (pseudo-?)JAMM/MPN fold; EMC8/9 are MPN-domain proteins related to the proteasome lid/COP9 deneddylase subunits but lack the catalytic metalloprotease residues (annotated CDD MPN_UPF0172, Pfam UPF0172) [file:human/EMC8/EMC8-uniprot.txt "DOMAIN 4..150"], [file:human/EMC8/EMC8-uniprot.txt "CDD; cd08060; MPN_UPF0172"].
Note: the context-provided "PDE6D-like phosphodiesterase fold" framing is NOT what the UniProt record states; the record annotates an MPN domain. No catalytic activity is assigned in UniProt. No moonlighting NMNAT/neuromuscular-junction role is substantiated in any of the EMC8 input files, so none is asserted.

Complex / structure

Identified as a component of the mammalian EMC ("mEMC") in the foundational ERAD-network MS study; EMC8 appears there under the alias COX4NB PMID:22119785. This is the IDA source for EMC-complex membership and cytoplasm localization.
Cryo-EM structures of human EMC place EMC8 (chain H) in the cytosolic-facing region of the complex [file:human/EMC8/EMC8-uniprot.txt "STRUCTURE BY ELECTRON MICROSCOPY (3.40 ANGSTROMS) OF THE EMC COMPLEX"]; the catalytic insertase machinery is the EMC3/EMC6 transmembrane vestibule, not EMC8 PMID:32439656.

Function (complex-level, not EMC8-intrinsic)

The EMC is a co- and post-translational transmembrane-domain insertase/chaperone that inserts newly synthesized membrane proteins into the ER membrane, with preference for weakly hydrophobic / destabilizing TMDs; handles multipass (stop-transfer) and tail-anchored substrates and sets N-exo topology of multipass proteins [file:human/EMC8/EMC8-uniprot.txt "enables the energy-independent insertion into endoplasmic reticulum membranes of newly synthesized membrane proteins"], [file:human/EMC8/EMC8-uniprot.txt "required for the post-translational insertion of tail-anchored/TA proteins in"].
These functional studies (PMID:29242231 insertase; PMID:29809151 cotranslational multipass; PMID:30415835 topogenesis; PMID:32439656/32459176 structure) concern the whole EMC. EMC8-specific IMP "membrane insertase activity" (GO:0032977, contributes_to) is appropriate because the GO contributes_to qualifier is exactly for a subunit contributing to a complex MF; full text of the IMP papers (knockdown of EMC subunits) was read by curators.

Interaction (IPI) annotations

All nine GO:0005515 protein binding IPI annotations have WITH/FROM = UniProtKB:Q15006 (EMC2) and come from high-throughput interactome / structural mapping papers (PMID:16189514 Rual Y2H map; 22119785 ERAD network; 26496610 BioPlex stoichiometry; 28514442 interactome communities; 30021884 histone XL-MS; 32296183 HuRI binary; 32439656 EMC structure; 33961781 BioPlex 3; 35271311 OpenCell). EMC2 is the EMC scaffold that EMC8 docks onto, so the interaction is real and biologically meaningful (it is how EMC8 joins the complex), but bare "protein binding" is uninformative -> KEEP_AS_NON_CORE per guidelines. The UniProt INTERACTION block confirms the EMC2 partner [file:human/EMC8/EMC8-uniprot.txt "O43402; Q15006: EMC2; NbExp=17"].
PMID:30021884 (histone crosslinking MS in nuclei) is an odd citation for an ER complex subunit, but it is a curator-entered IntAct EMC8-EMC2 evidence; cannot verify the specific datapoint from the abstract -> keep as non-core, do not REMOVE an experimental IPI.

Localization

ER membrane (peripheral, cytoplasmic side); also annotated cytoplasm (IDA, PMID:22119785) and ER (IDA/HPA). GO:0016020 membrane (HDA, PMID:19946888 NK-cell membrane proteome) is a generic parent, correct but low-information [file:human/EMC8/EMC8-uniprot.txt "SUBCELLULAR LOCATION: Endoplasmic reticulum membrane"].

Core function determination

For a non-catalytic cytosolic subunit, CORE = EMC complex membership (GO:0072546) + ER membrane (GO:0005789), with contributes_to membrane insertase activity (GO:0032977) capturing its participation in the complex MF.
The BP terms (GO:0045050 stop-transfer insertion; GO:0071816 TA insertion) are complex-level functions EMC8 contributes to; keep but they are complex-level, not EMC8-intrinsic.

Action summary

ACCEPT: EMC complex (all evidence forms), ER membrane, membrane insertase activity (contributes_to IMP/IBA), insertion BP terms (IDA/IMP/IBA), cytoplasm IDA, ER IDA.
KEEP_AS_NON_CORE: all 9 protein binding GO:0005515 IPI (bare term, but real EMC2 interaction); membrane HDA (generic parent).
No REMOVE/MODIFY/UNDECIDED warranted — annotations are consistent and well-supported.

Falcon deep-research findings (incorporated 2026-06)

EMC8-specific client docking (most important new finding): the cryo-EM structure of human EMC bound to a CaV1.2-CaVbeta3 ion-channel assembly intermediate shows EMC8 forms a defined cytosolic client-binding interface ("Cyto dock" / "EMC8 site", ~962 A^2, centered on EMC8's last helix) with CaVbeta3 PMID:37196677. PMID verified (Nature 2023). This establishes a direct EMC8-specific chaperone/assembly role, not just structural scaffolding.
EMC8 binding orders an otherwise-disordered CaVbeta region (Lys225-Ser245) via H-bond/salt-bridge networks involving conserved CaVbeta residues, supporting a holdase/assembly-stabilizing function PMID:37196677.
EMC8-EMC2 architecture: EMC2 forms an alpha-solenoid that clamps around EMC8 in the cytosolic basket; EMC8 (~23 kDa, ~44% identical to EMC9) and EMC9 are mutually exclusive (no ternary EMC2-EMC8-EMC9 complex forms) PMID:32459176. PMID verified (eLife 2020). Supports EMC8's cytosolic structural/assembly role and the paralog mutual-exclusivity already noted.
Review framing places EMC2/EMC8/EMC9 as the cytosolic subunits and EMC8/EMC9 as mutually exclusive paralogs of a cytosolic cradle engaging clients before insertion PMID:35287476. PMID verified (Annu Rev Biochem 2022).
ER-mitochondria contact context: EMC-VDAC1 cryo-EM (apo + VDAC1-bound) proposes a vestibule "gating plug" conformational switch; no EMC8-specific mechanistic role is assigned, so added only as low-relevance context PMID:38517390. PMID verified (Aging Albany NY 2024).
The Chen 2023 EMC8-CaVbeta3 evidence was added to the first core_function supported_by (EMC8 client-docking surface), alongside the O'Donnell 2020 EMC2-clamp evidence. No annotation actions changed; all additions are additive references/support.

Pn Notes

(EMC8-pn-notes.md)

EMC8 PN Consistency Notes

Generated: 2026-06-18
Project: PROTEOSTASIS
Scope: PN consistency rereview against local AIGR review and available deep-research artifacts
UniProt: O43402
AIGR review status: COMPLETE
Review batch: proteostasis-batch-2026-06-11
Batch change status: added

Source Files Checked

AIGR review YAML: present - genes/human/EMC8/EMC8-ai-review.yaml
AIGR review HTML: missing - genes/human/EMC8/EMC8-ai-review.html
Gene notes: present - genes/human/EMC8/EMC8-notes.md
GOA TSV: present - genes/human/EMC8/EMC8-goa.tsv
UniProt record: present - genes/human/EMC8/EMC8-uniprot.txt
PN dossier: projects/PROTEOSTASIS/reports/phase1_dossiers/EMC8.md
PN consistency section: projects/PROTEOSTASIS/reports/phase1_dossiers/_sections/EMC8.md
PN projection report: projects/PROTEOSTASIS/reports/pn_projection/pn_projected_gene_go_summary.tsv
PN mapping audit: projects/PROTEOSTASIS/reports/pn_mapping_audit/current_mapping_scrutiny.tsv

Deep Research Files

genes/human/EMC8/EMC8-deep-research-falcon.md

AIGR Review Snapshot

Description: EMC8 (ER membrane protein complex subunit 8; also known as C16orf2/C16orf4, COX4NB/NOC4 "Neighbor of COX4", FAM158B) is a small (210 aa) cytosolic, peripherally membrane-associated subunit of the endoplasmic reticulum membrane protein complex (EMC). The EMC is a conserved, nine-subunit ER transmembrane-domain insertase and membrane-protein chaperone that mediates energy-independent insertion of newly synthesized membrane proteins into the ER membrane, with a preference for transmembrane domains that are weakly hydrophobic or carry destabilizing charged/aromatic residues. The complex acts both co-translationally on multipass membrane proteins (where stop-transfer/membrane-anchor sequences become spanning helices, controlling N-exo topology of substrates such as G protein-coupled receptors) and post-translationally on tail-anchored proteins. Within EMC, EMC8 lies on the cytoplasmic face of the complex and is a non-catalytic accessory subunit; it contains an MPN domain (a JAMM/MPN-related fold) but lacks the catalytic metalloprotease residues, and the substrate-insertion vestibule is provided by the transmembrane subunits EMC3/EMC6 rather than by EMC8. EMC8 and its paralog EMC9 are mutually exclusive subunits that occupy the same position, defining alternative EMC variants. EMC8 docks onto the EMC2 scaffold subunit, its principal and well-documented protein interaction. EMC8 is broadly expressed across human tissues.
Existing/core annotation action counts: ACCEPT: 14; KEEP_AS_NON_CORE: 14

PN Consistency Summary

Consistency: Deep research, review YAML, and PN annotation agree: EMC8 is a cytosolic, non-catalytic accessory subunit docking on the EMC2 scaffold; mutually exclusive with paralog EMC9 (PMID:32459176). Degenerate MPN domain, no catalytic metalloprotease residues. The review adds an EMC8-specific client-docking ("Cyto dock"/CaVbeta3) chaperone surface (PMID:37196677) beyond the dossier; no contradiction.
PN story / NEW pressure: PN asserts only EMC membership + transmembrane import/insertion, already captured (GO:0072546 part_of; GO:0032977 contributes_to; GO:0045050, GO:0071816 involved_in). No NEW term warranted. The EMC8-specific CaVbeta3 chaperone/assembly surface could in principle motivate a chaperone MF, but the review (appropriately) leaves it as descriptive, not a new annotation — defensible.
Evidence alignment: High overlap — review and PN both rest on the EMC insertase/structure papers (22119785, 29242231, 32439656, 30415835, 32459176, 35287476). PN process claim is fully evidenced in the review.
Verdict: Consistent; thoroughly reviewed (incl. correct contributes_to for non-catalytic subunit). Only shared concern: group→GO:0044743 import mapping diverges from EMC insertion semantics.

Full Consistency Review

UniProt: O43402 · batch: proteostasis-batch-2026-06-11 · review status: COMPLETE
PN placement: ER proteostasis|Protein transport|Transmembrane protein import|EMC complex component ; PN-node mapping: type → GO:0072546 (EMC complex); group → GO:0044743 (protein transmembrane import into intracellular organelle); class → GO:0015031 (protein transport); branch=no_mapping.
Consistency: Deep research, review YAML, and PN annotation agree: EMC8 is a cytosolic, non-catalytic accessory subunit docking on the EMC2 scaffold; mutually exclusive with paralog EMC9 (PMID:32459176). Degenerate MPN domain, no catalytic metalloprotease residues. The review adds an EMC8-specific client-docking ("Cyto dock"/CaVbeta3) chaperone surface (PMID:37196677) beyond the dossier; no contradiction.
PN story / NEW pressure: PN asserts only EMC membership + transmembrane import/insertion, already captured (GO:0072546 part_of; GO:0032977 contributes_to; GO:0045050, GO:0071816 involved_in). No NEW term warranted. The EMC8-specific CaVbeta3 chaperone/assembly surface could in principle motivate a chaperone MF, but the review (appropriately) leaves it as descriptive, not a new annotation — defensible.
Mapping strategy: EMC8 does not change the shared node mapping; its EMC8/EMC9 mutual exclusivity makes both still "EMC complex" members, so GO:0072546 stands. Same group-level concern as EMC7: GO:0044743 (lumenal import) mismatches EMC membrane-protein insertion semantics (insertion terms are not subclasses of it).
Evidence alignment: High overlap — review and PN both rest on the EMC insertase/structure papers (22119785, 29242231, 32439656, 30415835, 32459176, 35287476). PN process claim is fully evidenced in the review.
Verdict: Consistent; thoroughly reviewed (incl. correct contributes_to for non-catalytic subunit). Only shared concern: group→GO:0044743 import mapping diverges from EMC insertion semantics.

PN Dossier Context

review_batch: proteostasis-batch-2026-06-11
review_yaml: genes/human/EMC8/EMC8-ai-review.yaml
PN workbook rows: 1

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

UniProt: O43402
In branches: ER
PN-node mapping records (path + ancestors):
- [type] ER proteostasis|Protein transport|Transmembrane protein import|EMC complex component
  status=mapped scope=ok_for_propagation_to_go GO=[GO:0072546 EMC complex]
  rationale: This PN type denotes ER membrane protein complex components. The GO EMC complex cellular-component term is the direct target.
- [group] ER proteostasis|Protein transport|Transmembrane protein import
  status=mapped scope=ok_for_propagation_to_go GO=[GO:0044743 protein transmembrane import into intracellular organelle]
  rationale: This PN group covers ER transmembrane-protein insertion/import systems such as EMC- and PAT-related pathways. The local GO cache does not expose an ER-specific matching term, so the broader intracellular-organelle transmembrane-import process is the best supported propagation target.
- [class] ER proteostasis|Protein transport
  status=mapped scope=ok_for_propagation_to_go GO=[GO:0015031 protein transport]
  rationale: The PN ER Protein transport class groups ER-targeting and ER-insertion pathways. GO protein transport is the appropriate propagation target, while the source class remains ER-specific and broader than any single GO transport subtype.
- [branch] ER proteostasis
  status=no_mapping scope= GO=[]
  rationale: Reviewed as a top-level PN branch. This is a systems/taxonomy umbrella, not a direct GO assertion; narrower child curations carry any propagating GO mappings.

Projected GO annotations (3)

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

Note

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

📄 View Raw YAML

id: O43402
gene_symbol: EMC8
product_type: PROTEIN
status: COMPLETE
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: 'EMC8 (ER membrane protein complex subunit 8; also known as C16orf2/C16orf4, COX4NB/NOC4 "Neighbor of COX4", FAM158B) is a small (210 aa) cytosolic, peripherally membrane-associated subunit of the endoplasmic reticulum membrane protein complex (EMC). The EMC is a conserved, nine-subunit ER transmembrane-domain insertase and membrane-protein chaperone that mediates energy-independent insertion of newly synthesized membrane proteins into the ER membrane, with a preference for transmembrane domains that are weakly hydrophobic or carry destabilizing charged/aromatic residues. The complex acts both co-translationally on multipass membrane proteins (where stop-transfer/membrane-anchor sequences become spanning helices, controlling N-exo topology of substrates such as G protein-coupled receptors) and post-translationally on tail-anchored proteins. Within EMC, EMC8 lies on the cytoplasmic face of the complex and is a non-catalytic accessory subunit; it contains an MPN domain (a JAMM/MPN-related fold) but lacks the catalytic metalloprotease residues, and the substrate-insertion vestibule is provided by the transmembrane subunits EMC3/EMC6 rather than by EMC8. EMC8 and its paralog EMC9 are mutually exclusive subunits that occupy the same position, defining alternative EMC variants. EMC8 docks onto the EMC2 scaffold subunit, its principal and well-documented protein interaction. EMC8 is broadly expressed across human tissues.'
alternative_products:
- name: '1'
  id: O43402-1
- name: '2'
  id: O43402-2
  sequence_note: VSP_045089
existing_annotations:
- term:
    id: GO:0032977
    label: membrane insertase activity
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: contributes_to
  review:
    summary: Phylogenetic (IBA) assignment of membrane insertase activity with the contributes_to qualifier, reflecting EMC8 participation in the EMC insertase complex rather than an intrinsic enzymatic activity of EMC8 itself.
    action: KEEP_AS_NON_CORE
    reason: Correct use of contributes_to for a non-catalytic subunit of the EMC insertase. EMC8 is a cytosolic accessory subunit and is not the catalytic insertase (the insertion vestibule is formed by EMC3/EMC6), so this complex-level MF is retained but not as the standalone core function. The core descriptor for EMC8 is EMC complex membership plus ER membrane localization.
    supported_by:
    - reference_id: file:human/EMC8/EMC8-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: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: Phylogenetic assignment of the EMC role in cotranslational insertion of multipass membrane proteins via stop-transfer/membrane-anchor sequences; a process EMC8 participates in as part of the complex.
    action: ACCEPT
    reason: Consistent with the experimentally supported EMC function; the complex mediates cotranslational insertion of multipass proteins in which stop-transfer anchors become membrane-spanning helices. This is a complex-level process EMC8 is involved in.
    supported_by:
    - reference_id: file:human/EMC8/EMC8-uniprot.txt
      supporting_text: cotranslational insertion of multi-pass membrane proteins in which
- term:
    id: GO:0071816
    label: tail-anchored membrane protein insertion into ER membrane
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: Phylogenetic assignment of the EMC role in post-translational insertion of tail-anchored proteins; EMC8 participates as part of the complex.
    action: ACCEPT
    reason: Consistent with experimental evidence that EMC is required for post-translational insertion of tail-anchored proteins into the ER membrane.
    supported_by:
    - reference_id: file:human/EMC8/EMC8-uniprot.txt
      supporting_text: post-translational insertion of tail-anchored/TA proteins in
- term:
    id: GO:0072546
    label: EMC complex
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: part_of
  review:
    summary: Phylogenetic assignment of EMC complex membership, the defining and core cellular-component association for EMC8.
    action: ACCEPT
    reason: Core localization/membership for EMC8; directly demonstrated experimentally (IDA PMID:22119785; IPI PMID:32439656) and conserved across the EMC8/EMC9 family.
    supported_by:
    - reference_id: file:human/EMC8/EMC8-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 localization from the UniProt subcellular location, consistent with EMC8 being a peripheral, cytoplasmic-side subunit of the ER-resident EMC.
    action: ACCEPT
    reason: Correct core compartment; EMC8 is a peripheral membrane protein at the ER membrane. Redundant with EXP/NAS ER membrane annotations.
    supported_by:
    - reference_id: file:human/EMC8/EMC8-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Endoplasmic reticulum membrane'
- term:
    id: GO:0072546
    label: EMC complex
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: part_of
  review:
    summary: InterPro-based (IPR005366, EMC8/9 family) electronic assignment to the EMC complex, consistent with the experimental membership annotation.
    action: ACCEPT
    reason: Correct core membership; redundant with IDA/IPI/IBA evidence for EMC complex membership.
    supported_by:
    - reference_id: file:human/EMC8/EMC8-uniprot.txt
      supporting_text: Component of the ER membrane protein complex (EMC)
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:16189514
  qualifier: enables
  review:
    summary: High-throughput yeast two-hybrid human interactome capturing the EMC8-EMC2 interaction (WITH/FROM UniProtKB:Q15006). Bare protein binding is uninformative, though the EMC2 partner is the scaffold EMC8 docks onto within the complex.
    action: KEEP_AS_NON_CORE
    reason: Records a real interaction with EMC2 (the EMC scaffold) but bare protein binding does not convey function; per guidelines not elevated to core. The functional content is captured by EMC complex membership.
    supported_by:
    - reference_id: file:human/EMC8/EMC8-uniprot.txt
      supporting_text: 'O43402; Q15006: EMC2; NbExp=17'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:22119785
  qualifier: enables
  review:
    summary: EMC8-EMC2 interaction (WITH/FROM UniProtKB:Q15006) from the integrative ERAD/EMC mapping study that originally placed EMC8 (as COX4NB) in the mammalian EMC. Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: Real, biologically meaningful interaction with the EMC2 scaffold, but the bare MF term is uninformative; the membership is better captured by GO:0072546.
    supported_by:
    - reference_id: file:human/EMC8/EMC8-uniprot.txt
      supporting_text: 'O43402; Q15006: EMC2; NbExp=17'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:26496610
  qualifier: enables
  review:
    summary: EMC8-EMC2 interaction (WITH/FROM UniProtKB:Q15006) from a quantitative stoichiometry-resolved interactome. Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: Genuine EMC2 interaction from a high-throughput study, but bare protein binding is uninformative; intra-EMC contact captured by complex membership.
    supported_by:
    - reference_id: file:human/EMC8/EMC8-uniprot.txt
      supporting_text: 'O43402; Q15006: EMC2; NbExp=17'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:28514442
  qualifier: enables
  review:
    summary: EMC8-EMC2 interaction (WITH/FROM UniProtKB:Q15006) from the BioPlex interactome/community analysis. Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: Real EMC2 interaction from a high-throughput AP-MS network, but bare protein binding is uninformative; not elevated to core.
    supported_by:
    - reference_id: file:human/EMC8/EMC8-uniprot.txt
      supporting_text: 'O43402; Q15006: EMC2; NbExp=17'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:30021884
  qualifier: enables
  review:
    summary: EMC8-EMC2 interaction (WITH/FROM UniProtKB:Q15006) entered into IntAct from a crosslinking-MS study. The paper title concerns histone interaction landscapes, an unexpected source, but the curated datapoint records an EMC8-EMC2 contact.
    action: KEEP_AS_NON_CORE
    reason: Curator-entered experimental IPI to the known EMC2 partner; per guidelines an experimental IPI is not removed merely because the abstract foregrounds a different topic. Bare protein binding remains uninformative, so kept as non-core.
    supported_by:
    - reference_id: file:human/EMC8/EMC8-uniprot.txt
      supporting_text: 'O43402; Q15006: EMC2; NbExp=17'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:32296183
  qualifier: enables
  review:
    summary: EMC8-EMC2 interaction (WITH/FROM UniProtKB:Q15006) from the HuRI reference binary interactome. Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: Genuine binary EMC2 interaction, but bare protein binding is uninformative; complex membership captures the functional content.
    supported_by:
    - reference_id: file:human/EMC8/EMC8-uniprot.txt
      supporting_text: 'O43402; Q15006: EMC2; NbExp=17'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:32439656
  qualifier: enables
  review:
    summary: EMC8-EMC2 interaction (WITH/FROM UniProtKB:Q15006) consistent with the cryo-EM structure of the human EMC, which resolves EMC8 contacting the EMC2 scaffold. Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: Structurally corroborated EMC2 interaction, but bare protein binding is uninformative; the structural membership is captured by GO:0072546 EMC complex.
    supported_by:
    - reference_id: file:human/EMC8/EMC8-uniprot.txt
      supporting_text: 'O43402; Q15006: EMC2; NbExp=17'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:33961781
  qualifier: enables
  review:
    summary: EMC8-EMC2 interaction (WITH/FROM UniProtKB:Q15006) from BioPlex 3 dual proteome-scale networks. Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: Real EMC2 interaction from a large AP-MS network, but bare protein binding is uninformative; not elevated to core.
    supported_by:
    - reference_id: file:human/EMC8/EMC8-uniprot.txt
      supporting_text: 'O43402; Q15006: EMC2; NbExp=17'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:35271311
  qualifier: enables
  review:
    summary: EMC8-EMC2 interaction (WITH/FROM UniProtKB:Q15006) from OpenCell endogenous-tagging interactome/localization. Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: Genuine endogenous EMC2 interaction, but bare protein binding is uninformative; the functional content is captured by EMC complex membership.
    supported_by:
    - reference_id: file:human/EMC8/EMC8-uniprot.txt
      supporting_text: 'O43402; Q15006: EMC2; NbExp=17'
- term:
    id: GO:0005783
    label: endoplasmic reticulum
  evidence_type: IDA
  original_reference_id: GO_REF:0000052
  qualifier: located_in
  review:
    summary: Direct immunofluorescence (HPA) evidence for ER localization, consistent with EMC8 being a subunit of the ER-resident EMC.
    action: ACCEPT
    reason: Correct compartment; the more specific ER membrane (GO:0005789) better captures the peripheral, cytoplasmic-side association of EMC8.
    supported_by:
    - reference_id: file:human/EMC8/EMC8-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Endoplasmic reticulum membrane'
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: NAS
  original_reference_id: PMID:29242231
  qualifier: located_in
  review:
    summary: ComplexPortal (NAS) assertion of EMC8 ER membrane localization, drawn from the EMC insertase characterization. Core compartment for EMC8.
    action: ACCEPT
    reason: Correct core compartment; EMC8 is a peripheral membrane protein on the cytoplasmic side of the ER membrane. Consistent with EXP/IEA ER membrane annotations.
    supported_by:
    - reference_id: file:human/EMC8/EMC8-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: ComplexPortal IDA for the EMC role in cotranslational insertion of multipass proteins via stop-transfer anchors; EMC8 participates as part of the complex.
    action: ACCEPT
    reason: Consistent with experimentally demonstrated EMC insertase function; a complex-level process EMC8 is involved in.
    supported_by:
    - reference_id: file:human/EMC8/EMC8-uniprot.txt
      supporting_text: cotranslational insertion of multi-pass membrane proteins in which
- 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: ComplexPortal IDA for the EMC role in post-translational insertion of tail-anchored proteins, the function for which Guna et al. demonstrated EMC is necessary and sufficient. EMC8 participates as part of the complex.
    action: ACCEPT
    reason: Directly supported by the reconstitution evidence that EMC inserts tail-anchored substrates; a complex-level process EMC8 is involved in.
    supported_by:
    - reference_id: file:human/EMC8/EMC8-uniprot.txt
      supporting_text: post-translational insertion of tail-anchored/TA proteins in
- term:
    id: GO:0072546
    label: EMC complex
  evidence_type: IPI
  original_reference_id: PMID:32439656
  qualifier: part_of
  review:
    summary: ComplexPortal IPI placing EMC8 in the EMC, corroborated by the cryo-EM structure of the human nine-subunit complex. Core membership.
    action: ACCEPT
    reason: Core, structurally demonstrated EMC complex membership; EMC8 (chain H) is resolved in the human EMC structures.
    supported_by:
    - reference_id: file:human/EMC8/EMC8-uniprot.txt
      supporting_text: ComplexPortal; CPX-5848; Endoplasmic reticulum membrane complex, EMC8 variant.
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: EXP
  original_reference_id: PMID:22119785
  qualifier: located_in
  review:
    summary: Experimental localization of EMC8 (identified as COX4NB) to the ER membrane in the integrative ERAD/EMC mapping study. Core compartment.
    action: ACCEPT
    reason: Core compartment supported by direct experimental evidence; EMC8 associates peripherally with the ER membrane as part of EMC.
    supported_by:
    - reference_id: PMID:22119785
      supporting_text: we identified 5 additional HCIPs (TTC35, TMEM32/MMGT1, TMEM85, C15orf24 and COX4NB)
- term:
    id: GO:0032977
    label: membrane insertase activity
  evidence_type: IMP
  original_reference_id: PMID:29809151
  qualifier: contributes_to
  review:
    summary: IMP (loss-of-function) evidence that EMC subunits contribute to the membrane insertase activity of the complex, assigned to EMC8 with the contributes_to qualifier. The full text (subunit perturbation in cotranslational multipass biogenesis) was read by the curator.
    action: KEEP_AS_NON_CORE
    reason: Appropriate contributes_to assignment for a non-catalytic accessory subunit of the EMC insertase. EMC8 is not itself catalytic (the EMC3/EMC6 vestibule performs insertion), so this complex-level MF is retained but not as the standalone core function. Not removed, since contributes_to is the intended qualifier for subunit contributions to a complex activity.
    supported_by:
    - reference_id: file:human/EMC8/EMC8-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 (EMC knockout/depletion in GPCR topogenesis) that the EMC has membrane insertase activity, assigned to EMC8 with contributes_to. Full text read by the curator.
    action: KEEP_AS_NON_CORE
    reason: Correct contributes_to assignment for a non-catalytic accessory subunit; the catalytic insertase activity is a property of the complex, not of EMC8 alone. Kept but not core for the individual subunit.
    supported_by:
    - reference_id: file:human/EMC8/EMC8-uniprot.txt
      supporting_text: the topology of multi-pass
- 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: IMP evidence that EMC (including EMC8) is required for cotranslational insertion of multipass membrane proteins via stop-transfer anchors.
    action: ACCEPT
    reason: Consistent with the experimentally supported EMC function; loss of EMC subunits impairs cotranslational multipass insertion. A complex-level process EMC8 is involved in.
    supported_by:
    - reference_id: file:human/EMC8/EMC8-uniprot.txt
      supporting_text: cotranslational insertion of multi-pass membrane proteins in which
- term:
    id: GO:0045050
    label: protein insertion into ER membrane by stop-transfer membrane-anchor sequence
  evidence_type: IMP
  original_reference_id: PMID:30415835
  qualifier: involved_in
  review:
    summary: IMP evidence (EMC knockout impairs accurate GPCR/multipass topogenesis) supporting the EMC role in cotranslational insertion via stop-transfer anchors; EMC8 participates as part of the complex.
    action: ACCEPT
    reason: Consistent with experimental topogenesis evidence; EMC mediates cotranslational insertion that sets multipass topology. A complex-level process EMC8 is involved in.
    supported_by:
    - reference_id: file:human/EMC8/EMC8-uniprot.txt
      supporting_text: the proper cotranslational insertion of N-terminal
- term:
    id: GO:0016020
    label: membrane
  evidence_type: HDA
  original_reference_id: PMID:19946888
  qualifier: located_in
  review:
    summary: High-throughput membrane-proteome (NK-cell) MS dataset assigning generic membrane localization. Correct but a generic parent of the ER membrane localization.
    action: KEEP_AS_NON_CORE
    reason: Accurate but low-information; the specific ER membrane (GO:0005789) better captures the localization of EMC8.
    supported_by:
    - reference_id: file:human/EMC8/EMC8-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Endoplasmic reticulum membrane'
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IDA
  original_reference_id: PMID:22119785
  qualifier: located_in
  review:
    summary: Direct evidence consistent with EMC8 being on the cytoplasmic side of the ER membrane; cytoplasm is a correct but less specific compartment than ER membrane.
    action: KEEP_AS_NON_CORE
    reason: Correct (EMC8 is a peripheral, cytoplasmic-side subunit) but generic; the ER membrane localization and EMC complex membership are the informative core terms.
    supported_by:
    - reference_id: file:human/EMC8/EMC8-uniprot.txt
      supporting_text: Cytoplasmic side
- term:
    id: GO:0072546
    label: EMC complex
  evidence_type: IDA
  original_reference_id: PMID:22119785
  qualifier: part_of
  review:
    summary: Direct experimental identification of EMC8 (as COX4NB) as a component of the mammalian EMC; the foundational evidence for the core complex membership of EMC8.
    action: ACCEPT
    reason: Core, directly demonstrated EMC complex membership; this is the defining cellular-component association for EMC8.
    supported_by:
    - reference_id: PMID:22119785
      supporting_text: we identified 5 additional HCIPs (TTC35, TMEM32/MMGT1, TMEM85, C15orf24 and COX4NB)
references:
- 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: GO_REF:0000052
  title: Gene Ontology annotation based on curation of immunofluorescence data
  findings: []
- id: PMID:16189514
  title: Towards a proteome-scale map of the human protein-protein interaction network.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: High-throughput Y2H interactome; source of an EMC8-EMC2 protein binding IPI. Not informative about the molecular function of EMC8 beyond complex membership.
- id: PMID:19946888
  title: Defining the membrane proteome of NK cells.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: NK-cell membrane proteome MS dataset; source of the generic membrane (GO:0016020) HDA annotation. Abstract-only in cache.
- id: PMID:22119785
  title: Defining human ERAD networks through an integrative mapping strategy.
  findings:
  - statement: Identified EMC8 (as COX4NB) as a high-confidence component of the mammalian ER membrane protein complex (mEMC), establishing EMC complex membership and ER membrane/cytoplasm localization.
    reference_section_type: RESULTS
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Foundational integrative MS study that placed EMC8 (COX4NB) in the mammalian EMC; source of the IDA EMC-complex membership and cytoplasm/ER membrane annotations.
- id: PMID:26496610
  title: A human interactome in three quantitative dimensions organized by stoichiometries and abundances.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: Quantitative interactome; source of an EMC8-EMC2 protein binding IPI. Background interaction data only.
- id: PMID:28514442
  title: Architecture of the human interactome defines protein communities and disease networks.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: BioPlex interactome/community analysis; source of an EMC8-EMC2 protein binding IPI.
- id: PMID:29242231
  title: The ER membrane protein complex is a transmembrane domain insertase.
  findings:
  - statement: The EMC is a transmembrane-domain insertase that catalyzes insertion of tail-anchored and other substrates into the ER membrane in a reconstituted system; EMC8 is a subunit of this complex.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Definitive demonstration that EMC is a TMD insertase; basis for the complex-level insertase MF and TA-insertion BP annotations EMC8 contributes to.
- id: PMID:29809151
  title: The ER membrane protein complex interacts cotranslationally to enable biogenesis of multipass membrane proteins.
  findings:
  - statement: EMC engages ribosomes cotranslationally and is required for biogenesis of multipass membrane proteins; depletion of EMC subunits impairs insertion.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Source of IMP membrane insertase activity (contributes_to) and cotranslational multipass insertion BP annotations.
- id: PMID:30021884
  title: Histone Interaction Landscapes Visualized by Crosslinking Mass Spectrometry in Intact Cell Nuclei.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: Crosslinking-MS study; an unexpected source for an ER-complex subunit, but curated in IntAct as an EMC8-EMC2 protein binding datapoint. Experimental IPI retained as non-core, not removed.
- id: PMID:30415835
  title: EMC Is Required to Initiate Accurate Membrane Protein Topogenesis.
  findings:
  - statement: EMC mediates cotranslational insertion of the first TMD of GPCRs and other multipass proteins and cooperates with Sec61 to ensure accurate topogenesis; EMC knockout impairs correct topology.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Source of IMP membrane insertase activity (contributes_to) and stop-transfer multipass insertion BP annotations.
- 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; source of an EMC8-EMC2 protein binding IPI.
- id: PMID:32439656
  title: Structural basis for membrane insertion by the human ER membrane protein complex.
  findings:
  - statement: Cryo-EM structure of the human nine-subunit EMC; substrate insertion occurs via an enclosed hydrophilic vestibule formed by EMC3 and EMC6, with EMC8 resolved as a cytosolic-facing subunit.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Structure of the human EMC (EMC8 variant); shows the catalytic vestibule is EMC3/EMC6, confirming EMC8 is a non-catalytic subunit. 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 3 interactome; source of an EMC8-EMC2 protein binding IPI.
- id: PMID:35271311
  title: 'OpenCell: Endogenous tagging for the cartography of human cellular organization.'
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: OpenCell endogenous-tagging interactome/localization; source of an EMC8-EMC2 protein binding IPI consistent with EMC membership.
- id: PMID:37196677
  title: 'EMC chaperone-Ca(V) structure reveals an ion channel assembly intermediate.'
  findings:
  - statement: Cryo-EM of human EMC bound to a CaV1.2-CaVbeta3 assembly intermediate; EMC8 forms a specific cytosolic client-docking interface ("Cyto dock"/"EMC8 site", ~962 A^2 centered on the last helix of EMC8) with CaVbeta3, binding two CaVbeta loops and ordering an otherwise disordered CaVbeta region, demonstrating an EMC8-specific chaperone/assembly role beyond generic insertion.
    reference_section_type: RESULTS
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: PubMed-verified (Nature 2023, PMID:37196677). Provides direct EMC8-specific structural evidence for a client-binding (CaVbeta3) surface, establishing a chaperone/assembly function for EMC8 distinct from the EMC3/EMC6 insertase core.
- id: PMID:32459176
  title: The architecture of EMC reveals a path for membrane protein insertion.
  findings:
  - statement: EMC2 forms an alpha-solenoid that clamps around EMC8 in the cytosolic basket; EMC8 is a ~23 kDa monomer ~44% identical to EMC9, and EMC8 and EMC9 are mutually exclusive subunits (no ternary EMC2-EMC8-EMC9 complex forms), supporting EMC8 as a structural assembly/scaffold subunit of the cytosolic module.
    reference_section_type: RESULTS
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: PubMed-verified (eLife 2020, PMID:32459176). Source of the EMC8-EMC2 clamp interaction and EMC8/EMC9 mutual exclusivity; supports EMC8's cytosolic structural/assembly role.
- 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 EMC2, EMC8, and EMC9 as the cytosolic subunits and EMC8/EMC9 as mutually exclusive paralogs of the cytosolic cradle that engages membrane-protein clients before insertion.
    reference_section_type: LITERATURE_REVIEW
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: PubMed-verified (Annu Rev Biochem 2022, PMID:35287476). Review supporting EMC8's cytosolic placement and EMC8/EMC9 paralog relationship already described in the review.
- 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 at mitochondria-ER contact sites, with a hydrophilic-vestibule "gating plug" conformational change proposed to regulate EMC function; EMC8 is a cytosolic subunit of the complexes studied (no EMC8-specific mechanistic role assigned in this study).
    reference_section_type: RESULTS
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: PubMed-verified (Aging (Albany NY) 2024, PMID:38517390). Structural study of EMC-VDAC1; does not assign an EMC8-specific role but provides context for alternative EMC functional states. Relevance to EMC8 specifically is low.
- id: file:human/EMC8/EMC8-uniprot.txt
  title: UniProt entry O43402 (EMC8_HUMAN), ER membrane protein complex subunit 8
  findings:
  - statement: EMC8 is a cytosolic, peripheral subunit (cytoplasmic side) of the ER membrane protein complex (EMC), an energy-independent TMD insertase for newly synthesized membrane proteins; mediates cotranslational multipass and post-translational tail-anchored insertion. EMC8 and EMC9 are mutually exclusive subunits; EMC8 belongs to the EMC8/EMC9 family and contains an MPN domain.
    reference_section_type: OTHER
core_functions:
- description: Cytosolic, non-catalytic accessory subunit of the ER membrane protein complex (EMC); its core role is to be a constitutive component of the EMC, an ER transmembrane-domain insertase/chaperone, docking onto the EMC2 scaffold on the cytoplasmic side of the ER membrane and providing a cytosolic client-docking surface (e.g., the EMC8 "Cyto dock" for CaVbeta3) during membrane-protein assembly.
  supported_by:
  - reference_id: file:human/EMC8/EMC8-uniprot.txt
    supporting_text: Component of the ER membrane protein complex (EMC)
  - reference_id: PMID:22119785
    supporting_text: we identified 5 additional HCIPs (TTC35, TMEM32/MMGT1, TMEM85, C15orf24 and COX4NB)
  in_complex:
    id: GO:0072546
    label: EMC complex
  locations:
  - id: GO:0005789
    label: endoplasmic reticulum membrane
- description: As part of the EMC, contributes to membrane insertase activity, participating in energy-independent insertion of newly synthesized membrane proteins into the ER membrane (cotranslational multipass insertion via stop-transfer anchors and post-translational tail-anchored protein insertion). EMC8 is not itself catalytic; the insertion vestibule is provided by EMC3/EMC6.
  contributes_to_molecular_function:
    id: GO:0032977
    label: membrane insertase activity
  locations:
  - id: GO:0005789
    label: endoplasmic reticulum membrane
  supported_by:
  - reference_id: file:human/EMC8/EMC8-uniprot.txt
    supporting_text: enables the energy-independent insertion into endoplasmic
  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 is the specific functional role of EMC8 (versus its mutually exclusive paralog EMC9) within the EMC, and do EMC8- and EMC9-containing complexes differ in substrate preference or regulation?
- question: Does the degenerate MPN domain of EMC8 retain any binding or regulatory function, or is it purely structural for incorporation into the complex?
suggested_experiments:
- description: Compare substrate-insertion profiles (e.g., ribosome profiling / proteomics of membrane-protein biogenesis) in EMC8-knockout versus EMC9-knockout versus EMC8/EMC9 double-knockout cells to define paralog-specific contributions to EMC function.
- description: Reconstitute EMC insertase activity in liposomes with and without EMC8 (and with EMC9 substituted) to test whether EMC8 is required for complex assembly, stability, or insertion efficiency of defined substrates.
- description: Use cryo-EM and crosslinking-MS to map the EMC8-EMC2 interface and determine how EMC8 incorporation affects the architecture of the cytosolic cap of the EMC.

EMC8

Gene Description

Existing Annotations Review

Core Functions

References

Suggested Questions for Experts

Suggested Experiments

Deep Research

Falcon

Comprehensive Research Report: Human EMC8 (UniProt O43402)—Functional Annotation

1) Identity verification (critical disambiguation)

2) Key concepts and definitions (current understanding)

2.1 The ER membrane protein complex (EMC)

2.2 EMC8: definition and placement within EMC

3) Molecular function of EMC8 within EMC: structure-informed mechanism

3.1 Structural role: EMC8 as part of the cytosolic cap/vestibule and assembly scaffold

3.2 Functional mapping: EMC8-proximal regions influence client-specific outcomes

4) Subcellular localization and topology

5) Experimental evidence linking EMC8/EMC to client insertion and chaperoning

5.1 Broad client spectrum: proteomics-defined EMC dependency and TMD features

5.2 2023–2024 high-impact developments: EMC8 in a client-bound assembly intermediate (CaV channels)

5.3 2024 structural development: EMC interaction with VDAC at ER–mitochondria contacts

6) Disease/phenotype associations and expert analysis (authoritative sources)

6.1 Expert consensus: why EMC perturbation can be pleiotropic

6.2 EMC8-specific human disease genetics: limited direct evidence in retrieved sources

7) Current applications and real-world implementations

8) Key statistics and data (from recent and foundational studies)

9) Summary: best-supported functional annotation for EMC8

Evidence summary table

Artifacts

Citations

📚 Additional Documentation

Notes

EMC8 (O43402) review notes

Identity / overview

Complex / structure

Function (complex-level, not EMC8-intrinsic)

Interaction (IPI) annotations

Localization

Core function determination

Action summary

Falcon deep-research findings (incorporated 2026-06)

Pn Notes

EMC8 PN Consistency Notes

Source Files Checked

Deep Research Files

AIGR Review Snapshot

PN Consistency Summary

Full Consistency Review

PN Dossier Context

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

Projected GO annotations (3)

Note

📄 View Raw YAML