Structural and mechanistic basis of the EMC-dependent biogenesis of distinct transmembrane clients

• Published in: eLife Vol. 9
• Main Authors: Miller-Vedam, Lakshmi E, Bräuning, Bastian, Popova, Katerina D, Schirle Oakdale, Nicole T, Bonnar, Jessica L, Prabu, Jesuraj R, Boydston, Elizabeth A, Sevillano, Natalia, Shurtleff, Matthew J, Stroud, Robert M, Craik, Charles S, Schulman, Brenda A, Frost, Adam, Weissman, Jonathan S
• Format: Journal Article
• Language: English
• Published: England eLife Sciences Publications, Ltd 25.11.2020; eLife Sciences Publications Ltd
• Subjects: Blotting, Western; Cell Biology; chaperone holdase; electron microscopy; EMC; endoplasmic reticulum; Endoplasmic Reticulum - metabolism; Humans; insertase; Intracellular Membranes - metabolism; membrane protein biogenesis; Membrane Proteins - biosynthesis; Membrane Proteins - genetics; Membrane Proteins - metabolism; Protein Structure, Tertiary; Saccharomyces cerevisiae - genetics; Saccharomyces cerevisiae Proteins - biosynthesis; Saccharomyces cerevisiae Proteins - genetics; Saccharomyces cerevisiae Proteins - metabolism; Sequence Alignment; Structural Biology and Molecular Biophysics; cell biology; chaperone holdase; electron microscopy; membrane protein biogenesis; EMC; structural biology; molecular biophysics; human; endoplasmic reticulum; S. cerevisiae; insertase
• ISSN: 2050-084X; 2050-084X
• DOI: 10.7554/eLife.62611

Membrane protein biogenesis in the endoplasmic reticulum (ER) is complex and failure-prone. The ER membrane protein complex (EMC), comprising eight conserved subunits, has emerged as a central player in this process. Yet, we have limited understanding of how EMC enables insertion and integrity of diverse clients, from tail-anchored to polytopic transmembrane proteins. Here, yeast and human EMC cryo-EM structures reveal conserved intricate assemblies and human-specific features associated with pathologies. Structure-based functional studies distinguish between two separable EMC activities, as an insertase regulating tail-anchored protein levels and a broader role in polytopic membrane protein biogenesis. These depend on mechanistically coupled yet spatially distinct regions including two lipid-accessible membrane cavities which confer client-specific regulation, and a non-insertase EMC function mediated by the EMC lumenal domain. Our studies illuminate the structural and mechanistic basis of EMC's multifunctionality and point to its role in differentially regulating the biogenesis of distinct client protein classes.