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

Miller-Vedam, L. E., Bräuning, B., Popova, K. D., Oakdale, N. T. S., Bonnar, J. L., Prabu, J. R., et al. (2020). Structural and mechanistic basis of the EMC-dependent biogenesis of distinct transmembrane clients. eLife, 9: e62611. doi:10.7554/eLife.62611.

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 Creators:
Miller-Vedam, Lakshmi E.1, Author
Bräuning, Bastian2, Author              
Popova, Katerina D.1, Author
Oakdale, Nicole T. Schirle1, Author
Bonnar, Jessica L.1, Author
Prabu, Jesuraj Rajan2, Author              
Boydston, Elizabeth A.1, Author
Sevillano, Natalia1, Author
Shurtleff, Matthew J.1, Author
Stroud, Robert M.1, Author
Craik, Charles S.1, Author
Schulman, Brenda A.2, Author              
Frost, Adam1, Author
Weissman, Jonathan S.1, Author
Affiliations:
1external, ou_persistent22              
2Schulman, Brenda / Molecular Machines and Signaling, Max Planck Institute of Biochemistry, Max Planck Society, ou_2466699              

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Free keywords: ER MEMBRANE-PROTEIN; BEAM-INDUCED MOTION; CRYO-EM; STRUCTURE PREDICTION; TETRATRICOPEPTIDE REPEAT; ZIKA VIRUS; TPR DOMAIN; I-TASSER; MODEL; IDENTIFICATIONLife Sciences & Biomedicine - Other Topics;
 Abstract: 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.

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Language(s): eng - English
 Dates: 2020
 Publication Status: Published online
 Pages: 47
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 Table of Contents: -
 Rev. Type: -
 Identifiers: ISI: 000606774500001
DOI: 10.7554/eLife.62611
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Project name : Leibniz Prize SCHU 3196/1-1
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Funding organization : Deutsche Forschungsgemeinschaft

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Title: eLife
Source Genre: Journal
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Publ. Info: Cambridge : eLife Sciences Publications
Pages: - Volume / Issue: 9 Sequence Number: e62611 Start / End Page: - Identifier: ISSN: 2050-084X
CoNE: https://pure.mpg.de/cone/journals/resource/2050-084X