| Topic | Key findings | Key quantitative/statistical details | Key sources with publication year and URL | Citation IDs |
|---|---|---|---|---|
| Identity / localization | Human EMC4 is ER membrane protein complex subunit 4, encoded by EMC4 (ENSG00000128463), matching UniProt Q5J8M3. EMC is an ER-localized multi-subunit insertase/chaperone complex required for membrane protein biogenesis. | Human EMC described as 9-subunit; complex dimensions reported at ~200 × 70 × 100 Å in one cryo-EM study. | Open Targets EMC4 target entry; Pleiner et al., 2020, Science, https://doi.org/10.1126/science.abb5008; O'Donnell et al., 2020, eLife, https://doi.org/10.7554/elife.57887 | (pqac-00000000, pqac-00000003, pqac-00000007) |
| Structure / topology of EMC4 | EMC4 is a membrane subunit adjacent to the EMC3/EMC6 insertase core. Improved human cryo-EM maps assigned 3 EMC4 transmembrane helices, and EMC4 also contributes a C-terminal β-strand that completes an EMC1 membrane-proximal β-propeller, indicating structural roles in both the membrane and lumenal domains. | 3 TMDs assigned to EMC4 in 2023 human structure; vestibule partly enclosed by 5 dynamic TMDs from EMC4/7/10. | Pleiner et al., 2023, J Cell Biol, https://doi.org/10.1083/jcb.202212007; Li et al., 2024, Aging (Albany NY), https://doi.org/10.18632/aging.205660; Pleiner et al., 2020, Science, https://doi.org/10.1126/science.abb5008 | (pqac-00000013, pqac-00000014, pqac-00000015, pqac-00000005, pqac-00000017) |
| Insertase mechanism | EMC acts as a co- and post-translational insertase for transmembrane helices, especially weakly hydrophobic tail-anchored TMDs and some multipass membrane proteins. Mechanistically, EMC3/EMC6 form a hydrophilic vestibule that lowers the energetic barrier to membrane insertion, while EMC4 helps shape/enclose this insertion environment. | Cryo-EM resolutions reported at 3.4 Å overall for human EMC; vestibule includes conserved positive charges and a methionine-rich capture loop; membrane proteins comprise ~20–25% of eukaryotic/human genes according to review/background. | Pleiner et al., 2020, Science, https://doi.org/10.1126/science.abb5008; O'Donnell et al., 2020, eLife, https://doi.org/10.7554/elife.57887; Bai et al., 2020, Nature, https://doi.org/10.1038/s41586-020-2389-3; Hegde, 2022, Annu Rev Biochem, https://doi.org/10.1146/annurev-biochem-032620-104553 | (pqac-00000002, pqac-00000003, pqac-00000004, pqac-00000007, pqac-00000017) |
| EMC4 role in vestibule architecture / substrate contacts | EMC4 partially encloses only the hydrophilic vestibule side of EMC, and substrate photocrosslinking/disulfide-crosslinking showed contacts with EMC4 as well as EMC3. EMC4 loss also impairs incorporation of EMC7 and EMC10, indicating EMC4 helps assemble the vestibule-enclosing module. | Disulfide formation interpreted at ~3–5 Å proximity; crosslinking detected for EMC3 and EMC4; complete EMC4 loss impaired EMC7/EMC10 assembly. | Pleiner et al., 2023, J Cell Biol, https://doi.org/10.1083/jcb.202212007 | (pqac-00000013, pqac-00000014, pqac-00000015) |
| Selectivity filter / topology control | EMC contains a positively charged hydrophilic vestibule that acts as a selectivity filter, repelling substrates with positively charged soluble domains and limiting misinsertion of mitochondrial TA proteins while helping enforce correct topology of multipass substrates. EMC4 contributes the sidewall/enclosure of this vestibule rather than the key charged residues themselves. | Analysis included 709 human GPCR sequences; even a single added positive charge to an SQS reporter strongly reduced ER insertion; electrostatic potential mapped from −3 to +3 kT/e; EMC3 R31/R180 mutants altered selectivity. | Pleiner et al., 2023, J Cell Biol, https://doi.org/10.1083/jcb.202212007 | (pqac-00000013, pqac-00000018, pqac-00000020) |
| Chaperone / assembly role for multipass proteins | Beyond insertase activity, EMC also functions as a holdase/chaperone for complex multipass clients. In the CaV1.2 assembly intermediate, EMC4 participates in the EMC client-binding/chaperone architecture and in the lumenal EMC1/4/7/10 module that supports a transmembrane docking site during channel assembly. | EMC–CaV1.2(ΔC)–CaVβ3 complex mass ~0.6 MDa; cryo-EM maps at 3.4 Å and 3.3 Å; Cyto dock ~1,500 Ų with EMC8 site 962 Ų and EMC2 site 550 Ų. | Chen et al., 2023, Nature, https://doi.org/10.1038/s41586-023-06175-5; Miller-Vedam et al., 2020, eLife, https://doi.org/10.1101/2020.09.02.280008 | (pqac-00000021, pqac-00000022, pqac-00000023, pqac-00000006) |
| Peripheral versus structural-essential subunit behavior | EMC4 is not as globally assembly-critical as EMC2, but it is not merely dispensable: EMC4 depletion leaves many other EMC subunits stable, yet phenocopies client defects and contributes directly to insertion/chaperone functions. Reviews and knockdown studies therefore place EMC4 among more peripheral subunits with specific mechanistic importance. | In one proteomic study, 11 proteins decreased ≥2-fold in both EMC2- and EMC4-depleted cells, and 10/11 had at least one TMD; EMC4 knockdown had no effect on abundance of other EMC members in that dataset. | Shurtleff et al., 2018, eLife, https://doi.org/10.7554/elife.37018; Chitwood & Hegde, 2019, Trends Cell Biol, https://doi.org/10.1016/j.tcb.2019.01.007 | (pqac-00000010, pqac-00000012) |
| Client/substrate classes and pathways | EMC/EMC4 support biogenesis of tail-anchored proteins (e.g., SQS/FDFT1), sterol-related enzymes, GPCRs, ion channels, and diverse multipass transporters/secretory membrane proteins. EMC-dependent biology therefore connects EMC4 to membrane protein proteostasis, sterol/cholesterol homeostasis, and ER quality-control pathways. | Yeast TMT proteomics identified 38 likely EMC clients; mammalian depletion studies found 11 proteins reduced ≥2-fold in both EMC2 and EMC4 knockdown backgrounds. | Bai et al., 2020, Nature, https://doi.org/10.1038/s41586-020-2389-3; Volkmar et al., 2019, J Cell Sci, https://doi.org/10.1242/jcs.223453; Shurtleff et al., 2018, eLife, https://doi.org/10.7554/elife.37018 | (pqac-00000004, pqac-00000010) |
| Lipid scrambling hypothesis | Recent computational/biophysical work suggests lipid scrambling may be a general property of insertases and localizes EMC scrambling activity specifically to Emc3 and Emc4 in silico. This supports a model in which EMC4 helps create a hydrophilic pathway used for both protein insertion and lipid flip-flop. | >150 proteins/complexes tested in silico; scrambling criterion used lipid angle >125° (upper leaflet) or <55° (lower leaflet); BSA back-extraction assay typically reduced NBD fluorescence by ~50% (practically 35–45%). | Li et al., 2024, PNAS, https://doi.org/10.1073/pnas.2319476121 | (pqac-00000033, pqac-00000034, pqac-00000035) |
| Viral host-factor role: flaviviruses | EMC4 is a validated proviral host factor for dengue, yellow fever, and Zika viruses. EMC4 supports infection at least at two stages: an early step at or before uncoating and a later step in viral membrane-protein biogenesis, including NS4B-associated processes. | EMC4-targeting sgRNAs reduced YFV infectivity ~5–20-fold; EMC4 KO caused up to 3 log10 lower YFV titers by 33.5 hpi; DENV2/DENV4 production fell below detection; anti-EMC4 siRNAs reduced ZIKV replicon RNA by ~54–55% with 73% or 94% EMC4 knockdown. | Barrows et al., 2019, Sci Rep, https://doi.org/10.1038/s41598-019-45910-9; Lin et al., 2019, Cell Reports, https://doi.org/10.1016/j.celrep.2019.04.051; Verhaegen & Vermeire, 2024, npj Viruses, https://doi.org/10.1038/s44298-024-00031-7 | (pqac-00000011, pqac-00000029, pqac-00000030, pqac-00000031, pqac-00000032) |
| Viral host-factor role: SV40 / organelle tethering | EMC4 also has a more selective EMC-independent or EMC-submodule-like role in SV40 entry, where EMC4 and EMC7 promote late endosome-to-ER transport. EMC4 engages Rab7 and syntaxin18 and was proposed to act as a molecular tether stabilizing LE–ER contacts needed for viral trafficking. | EMC4 knockdown blocked SV40 infection; siRNA-resistant EMC4-FLAG fully rescued infection in the reported assays. | Bagchi et al., 2020, Nat Commun, https://doi.org/10.1038/s41467-020-14967-w | (pqac-00000009) |
| Disease / phenotype associations | Direct monogenic human disease attribution for EMC4 itself remains limited in the retrieved evidence, but EMC4 is linked through EMC biology to neurodegeneration-related screening signals, lysosomal storage disease, Alzheimer disease, Parkinson disease, and dengue disease in Open Targets evidence aggregation. Expert reviews emphasize broader EMC involvement in membrane-protein folding diseases and cholesterol-homeostasis phenotypes rather than EMC4-specific clinical syndromes. | Open Targets evidence sizes shown as 5 for the listed EMC4 disease associations; no clinical trials were retrieved. | Open Targets EMC4 associations; Hegde, 2022, Annu Rev Biochem, https://doi.org/10.1146/annurev-biochem-032620-104553; Volkmar et al., 2019, J Cell Sci, https://doi.org/10.1242/jcs.223453 | (pqac-00000000, pqac-00000012) |


*Table: This table summarizes the main experimentally supported roles of human EMC4 within the ER membrane protein complex, including structure, mechanism, client classes, and disease-relevant phenotypes. It is useful as a compact evidence map linking EMC4-specific findings to broader EMC biology.*