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TitleThe ER membrane protein complex acts as a chaperone to promote the biogenesis of multi-bundle membrane proteins.
Journal, issue, pagesbioRxiv, Year 2026
Publish dateJan 15, 2026
AuthorsMarinda Stanton / Bharti Singal / Mahamaya Biswal / Megha Agarwal / Caroline Elizabeth Scheuing / Gerardo Dasaev Vargas / Alex Gao / Casey A Gifford / Tino Pleiner /
PubMed AbstractNearly half of the ~5,000 human membrane proteins need to assemble into stoichiometric complexes as part of their biogenesis at the endoplasmic reticulum (ER) membrane. How ER resident biogenesis ...Nearly half of the ~5,000 human membrane proteins need to assemble into stoichiometric complexes as part of their biogenesis at the endoplasmic reticulum (ER) membrane. How ER resident biogenesis factors coordinate membrane insertion, folding and assembly is not well understood. Here, we demonstrate that the ER membrane protein complex (EMC) insertase additionally acts as a chaperone to facilitate the assembly of heterotrimeric voltage-gated calcium channels (Ca). Using function-separating mutations and inhibitory nanobodies we show that nascent Ca channels are degraded prematurely when EMC's chaperone function is selectively perturbed. Blocking EMC's chaperone function strongly impaired Ca-dependent cardiomyocyte contraction. EMC engagement of the pore-forming Caα-subunit occurred co-translationally and required Caα's first transmembrane domain bundle to protrude from the nascent ribosome•Sec61•multipass translocon complex. Our findings establish a chaperone function for the EMC and reveal that biogenesis of multi-bundle membrane proteins requires a highly orchestrated, co-translational interplay between ER biogenesis factors.
External linksbioRxiv / PubMed:41648177 / PubMed Central
MethodsEM (single particle)
Resolution4.16 Å
Structure data

74981

9zz6

EMDB-74981, PDB-9zz6:
The ER membrane protein complex acts as a chaperone to promote voltage-gated calcium channel assembly
Method: EM (single particle) / Resolution: 4.16 Å

Chemicals

ChemComp-NAG:
2-acetamido-2-deoxy-beta-D-glucopyranose

Source
  • homo sapiens (human)
  • lama glama (llama)
KeywordsCHAPERONE/IMMUNE SYSTEM / protein biogenesis / endoplasmic reticulum / ER / chaperone / insertase / complex / membrane protein / CHAPERONE-IMMUNE SYSTEM complex

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