Multiple selection filters ensure accurate tail-anchored membrane protein targeting

  1. Meera Rao
  2. Voytek Okreglak
  3. Un Seng Chio
  4. Hyunju Cho
  5. Peter Walter
  6. Shu-ou Shan  Is a corresponding author
  1. California Institute of Technology, United States
  2. Howard Hughes Medical Institute, University of California, San Francisco, United States

Abstract

Accurate protein localization is crucial to generate and maintain organization in all cells. Achieving accuracy is challenging, as the molecular signals that dictate a protein's cellular destination are often promiscuous. A salient example is the targeting of an essential class of tail-anchored (TA) proteins, whose sole defining feature is a transmembrane domain near their C-terminus. Here we show that the Guided Entry of Tail-anchored protein (GET) pathway selects TA proteins destined to the endoplasmic reticulum (ER) utilizing distinct molecular steps, including differential binding by the co-chaperone Sgt2 and kinetic proofreading after ATP hydrolysis by the targeting factor Get3. Further, the different steps select for distinct physicochemical features of the TA substrate. The use of multiple selection filters may be general to protein biogenesis pathways that must distinguish correct and incorrect substrates based on minor differences.

Article and author information

Author details

  1. Meera Rao

    Division of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Voytek Okreglak

    Department of Biochemistry and Biophysics, Howard Hughes Medical Institute, University of California, San Francisco, San Francisco, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Un Seng Chio

    Division of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Hyunju Cho

    Division of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Peter Walter

    Department of Biochemistry and Biophysics, Howard Hughes Medical Institute, 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:" 0000-0002-6849-708X
  6. Shu-ou Shan

    Division of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, United States
    For correspondence
    sshan@caltech.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-6526-1733

Funding

National Institutes of Health (GM107368)

  • Meera Rao
  • Un Seng Chio
  • Hyunju Cho
  • Shu-ou Shan

Howard Hughes Medical Institute

  • Peter Walter

Gordon and Betty Moore Foundation (GBMF2939)

  • Shu-ou Shan

Leukemia and Lymphoma Society

  • Voytek Okreglak

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Reid Gilmore, University of Massachusetts Medical School, United States

Publication history

  1. Received: September 6, 2016
  2. Accepted: December 6, 2016
  3. Accepted Manuscript published: December 7, 2016 (version 1)
  4. Version of Record published: January 5, 2017 (version 2)

Copyright

© 2016, Rao 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. Meera Rao
  2. Voytek Okreglak
  3. Un Seng Chio
  4. Hyunju Cho
  5. Peter Walter
  6. Shu-ou Shan
(2016)
Multiple selection filters ensure accurate tail-anchored membrane protein targeting
eLife 5:e21301.
https://doi.org/10.7554/eLife.21301

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