The architecture of EMC reveals a path for membrane protein insertion.
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Peer-reviewed
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Abstract
Approximately 25% of eukaryotic genes code for integral membrane proteins that are assembled at the endoplasmic reticulum. An abundant and widely conserved multi-protein complex termed EMC has been implicated in membrane protein biogenesis, but its mechanism of action is poorly understood. Here, we define the composition and architecture of human EMC using biochemical assays, crystallography of individual subunits, site-specific photocrosslinking, and cryo-EM reconstruction. Our results suggest that EMC's cytosolic domain contains a large, moderately hydrophobic vestibule that can bind a substrate's transmembrane domain (TMD). The cytosolic vestibule leads into a lumenally-sealed, lipid-exposed intramembrane groove large enough to accommodate a single substrate TMD. A gap between the cytosolic vestibule and intramembrane groove provides a potential path for substrate egress from EMC. These findings suggest how EMC facilitates energy-independent membrane insertion of TMDs, explain why only short lumenal domains are translocated by EMC, and constrain models of EMC's proposed chaperone function.
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Funder: Boehringer Ingelheim Fonds; FundRef: http://dx.doi.org/10.13039/501100001645
Funder: Naito Foundation; FundRef: http://dx.doi.org/10.13039/100007428
Funder: Japanese Biochemical Society
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2050-084X
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Medical Research Council (MC_UP_1201/10)
National Institutes of Health (R01 GM078186)
National Institutes of Health (R01 GM130051)
European Molecular Biology Organization (ALTF 18-2018)
Swiss National Science Foundation (P2ELP3_18910)