The ER membrane protein complex interacts cotranslationally to enable biogenesis of multipass membrane proteins
- University of California, San Francisco, United States
- Max Planck Institute of Biochemistry, Germany
- University of Pittsburgh, United States
Abstract
The endoplasmic reticulum (ER) supports biosynthesis of proteins with diverse transmembrane domain (TMD) lengths and hydrophobicity. Features in transmembrane domains such as charged residues in ion channels are often functionally important, but could pose a challenge during cotranslational membrane insertion and folding. Our systematic proteomic approaches in both yeast and human cells revealed that the ER membrane protein complex (EMC) binds to and promotes the biogenesis of a range of multipass transmembrane proteins, with a particular enrichment for transporters. Proximity-specific ribosome profiling demonstrates that the EMC engages clients cotranslationally and immediately following clusters of TMDs enriched for charged residues. The EMC can remain associated after completion of translation, which both protects clients from premature degradation and allows recruitment of substrate-specific and general chaperones. Thus, the EMC broadly enables the biogenesis of multipass transmembrane proteins containing destabilizing features, thereby mitigating the trade-off between function and stability.
Data availability
Sequencing data have been deposited in GEO under accession code GSE112891.
-
The ER membrane protein complex interacts cotranslationally to enable biogenesis of multipass membrane proteinsPublicly available at the NCBI Gene Expression Omnibus (accession no: GSE112891).
-
The SND proteins constitute an alternative targeting route to the endoplasmic reticulumPublicly available at the NCBI Gene Expression Omnibus (accession no: GSE85686).
-
Principles of ER Co-Translational Translocation Revealed by Proximity-Specific Ribosome ProfilingPublicly available at the NCBI Gene Expression Omnibus (accession no: GSE61012).
Article and author information
Author details
Jonathan S Weissman
Funding
Howard Hughes Medical Institute (Investigator Program)
- Jonathan S Weissman
Deutsche Forschungsgemeinschaft (Gottfried Wilhelm Leibniz Prize MA 1764/2-1)
- Georg HH Borner
European Research Council (ERC2012-SyG_318987-ToPAG)
- Daniel N Itzhak
Howard Hughes Medical Institute (Faculty Scholar Grant)
- Adam Frost
National Institutes of Health (AG041826)
- Jonathan S Weissman
National Institutes of Health (1DP2GM110772-01)
- Adam Frost
National Institutes of Health (8P41GM103481)
- Alma L Burlingame
National Institutes of Health (1S10OD16229)
- Alma L Burlingame
National Institutes of Health (GM075061)
- Jeffrey Brodsky
Helen Hay Whitney Foundation (Postdoctoral Fellowship)
- Matthew J Shurtleff
Jane Coffin Childs Memorial Fund for Medical Research (Postdoctoral Fellowship)
- Nicole T Schirle Oakdale
Sandler Foundation (Program for Breakthrough Biomedical Research)
- Adam Frost
American Asthma Foundation
- Adam Frost
Louis-Jeantet Foundation
- Daniel N Itzhak
Dr. Miriam and Sheldon G. Adelson Medical Research Foundation
- Alma L Burlingame
Max Planck Society for the Advancement of Science
- Daniel N Itzhak
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Copyright
© 2018, Shurtleff et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
Metrics
-
- 14,148
- views
-
- 1,792
- downloads
-
- 205
- citations
Views, downloads and citations are aggregated across all versions of this paper published by eLife.
Download links
A two-part list of links to download the article, or parts of the article, in various formats.
Downloads (link to download the article as PDF)
Open citations (links to open the citations from this article in various online reference manager services)
Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)
The ER membrane protein complex interacts cotranslationally to enable biogenesis of multipass membrane proteins
eLife 7:e37018.
https://doi.org/10.7554/eLife.37018
