EMC chaperone activity is required for cotranslational calcium channel assembly

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 human ER membrane protein complex (EMC) insertase additionally acts as a chaperone to facilitate the assembly of heterotrimeric voltage-gated calcium channels (Cav). Using function-separating mutations and inhibitory nanobodies, we show that nascent Cav channels are degraded prematurely when EMC’s chaperone function is selectively perturbed. Blocking EMC’s chaperone function impaired Cav-dependent cardiomyocyte contraction. EMC engagement of the pore-forming Cav α-subunit occurred cotranslationally and required the Cav α-subunit’s first transmembrane domain bundle to protrude from the nascent ribosome–multipass translocon complex. Our findings establish a chaperone function for the EMC and suggest that biogenesis of multibundle membrane proteins may require a highly orchestrated, cotranslational interplay among ER biogenesis factors. Stanton et al. show that the human endoplasmic reticulum membrane protein complex (EMC) engages nascent calcium channels cotranslationally as a chaperone as part of a large ribosome–multipass translocon–EMC supercomplex. Loss of this function impairs channel biogenesis and disrupts cardiomyocyte contraction.