Journal
SCIENCE
Volume 369, Issue 6502, Pages 433-+Publisher
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/science.abb5008
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Funding
- Heritage Medical Research Institute
- Kinship Foundation
- Pew-Stewart Foundation
- NIH's National Institute of General Medical Sciences [DP2GM137412]
- Deutsche Forschungsgemeinschaft
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A defining step in the biogenesis of a membrane protein is the insertion of its hydrophobic transmembrane helices into the lipid bilayer. The nine-subunit endoplasmic reticulum (ER) membrane protein complex (EMC) is a conserved co- and posttranslational insertase at the ER. We determined the structure of the human EMC in a lipid nanodisc to an overall resolution of 3.4 angstroms by cryo-electron microscopy, permitting building of a nearly complete atomic model. We used structure-guided mutagenesis to demonstrate that substrate insertion requires a methionine-rich cytosolic loop and occurs via an enclosed hydrophilic vestibule within the membrane formed by the subunits EMC3 and EMC6. We propose that the EMC uses local membrane thinning and a positively charged patch to decrease the energetic barrier for insertion into the bilayer.
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