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

• Published in: Science (American Association for the Advancement of Science) Vol. 369; no. 6502; pp. 433 - 436
• Main Authors: Pleiner, Tino, Tomaleri, Giovani Pinton, Januszyk, Kurt, Inglis, Alison J, Hazu, Masami, Voorhees, Rebecca M
• Format: Journal Article
• Language: English
• Published: United States The American Association for the Advancement of Science 24-07-2020
• Subjects: Biosynthesis; Electron microscopy; Endoplasmic reticulum; Endoplasmic Reticulum - chemistry; Endoplasmic Reticulum - metabolism; Endoplasmic Reticulum - ultrastructure; Humans; Integral membrane proteins; Intracellular Membranes - chemistry; Intracellular Membranes - metabolism; Intracellular Membranes - ultrastructure; Lipid Bilayers - chemistry; Lipid Bilayers - metabolism; Lipids; Membrane Proteins - chemistry; Membrane Proteins - metabolism; Membrane Proteins - ultrastructure; Membranes; Microscopy; Multiprotein Complexes - chemistry; Multiprotein Complexes - metabolism; Multiprotein Complexes - ultrastructure; Proteins; Proteomes
• ISSN: 0036-8075; 1095-9203
• DOI: 10.1126/science.abb5008

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.