Structural basis for membrane insertion by the human ER membrane protein complex

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Science  24 Jul 2020:
Vol. 369, Issue 6502, pp. 433-436
DOI: 10.1126/science.abb5008

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A membrane protein insertion complex

Membrane proteins make up one-quarter of the human proteome and are required for all aspects of cell-to-cell communication, signaling, and transport. Defects in membrane protein biogenesis underlie a variety of human diseases, and half of all therapeutic drugs target an integral membrane protein. Pleiner et al. describe the cryo–electron microscopy structure of the human endoplasmic reticulum (ER) membrane protein complex, a large oligomeric assembly involved in the biogenesis of membrane proteins in the ER. This structure helps to explain how this complex captures and then inserts nascent proteins into the lipid bilayer, elucidating the molecular details of a fundamental biological process with broad biomedical implications.

Science, this issue p. 433


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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