The ER membrane protein complex interacts cotranslationally to enable biogenesis of multipass membrane proteins

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 following data sets were generated
The following previously published data sets were used

Article and author information

Author details

  1. Matthew J Shurtleff

    Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Daniel N Itzhak

    Department of Proteomics and Signal Transduction, Max Planck Institute of Biochemistry, Martinsried, Germany
    Competing interests
    The authors declare that no competing interests exist.
  3. Jeffrey A Hussmann

    Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Nicole T Schirle Oakdale

    Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Elizabeth A Costa

    Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-8365-0436
  6. Martin Jonikas

    Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Jimena Weibezahn

    Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, United States
    Competing interests
    The authors declare that no competing interests exist.
  8. Katerina D Popova

    Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, United States
    Competing interests
    The authors declare that no competing interests exist.
  9. Calvin H Jan

    Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, United States
    Competing interests
    The authors declare that no competing interests exist.
  10. Pavel Sinitcyn

    Department of Proteomics and Signal Transduction, Max Planck Institute of Biochemistry, Martinsried, Germany
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-2653-1702
  11. Shruthi S Vembar

    Department of Biological Sciences, University of Pittsburgh, Pittsburgh, United States
    Competing interests
    The authors declare that no competing interests exist.
  12. Hilda Hernandez

    Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, United States
    Competing interests
    The authors declare that no competing interests exist.
  13. Jürgen Cox

    Department of Proteomics and Signal Transduction, Max Planck Institute of Biochemistry, Martinsried, Germany
    Competing interests
    The authors declare that no competing interests exist.
  14. Alma L Burlingame

    Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, United States
    Competing interests
    The authors declare that no competing interests exist.
  15. Jeffrey Brodsky

    Department of Biological Sciences, University of Pittsburgh, Pittsburgh, United States
    Competing interests
    The authors declare that no competing interests exist.
  16. Adam Frost

    Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-2231-2577
  17. Georg HH Borner

    Department of Proteomics and Signal Transduction, Max Planck Institute of Biochemistry, Martinsried, Germany
    For correspondence
    borner@biochem.mpg.de
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-3166-3435
  18. Jonathan S Weissman

    Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, United States
    For correspondence
    Jonathan.Weissman@ucsf.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-2445-670X

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.

Reviewing Editor

  1. David Ron, University of Cambridge, United Kingdom

Publication history

  1. Received: March 27, 2018
  2. Accepted: May 26, 2018
  3. Accepted Manuscript published: May 29, 2018 (version 1)
  4. Version of Record published: June 11, 2018 (version 2)
  5. Version of Record updated: August 6, 2018 (version 3)

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.

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  1. Matthew J Shurtleff
  2. Daniel N Itzhak
  3. Jeffrey A Hussmann
  4. Nicole T Schirle Oakdale
  5. Elizabeth A Costa
  6. Martin Jonikas
  7. Jimena Weibezahn
  8. Katerina D Popova
  9. Calvin H Jan
  10. Pavel Sinitcyn
  11. Shruthi S Vembar
  12. Hilda Hernandez
  13. Jürgen Cox
  14. Alma L Burlingame
  15. Jeffrey Brodsky
  16. Adam Frost
  17. Georg HH Borner
  18. Jonathan S Weissman
(2018)
The ER membrane protein complex interacts cotranslationally to enable biogenesis of multipass membrane proteins
eLife 7:e37018.
https://doi.org/10.7554/eLife.37018
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