1. Biochemistry and Chemical Biology
  2. Cell Biology
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Structure and topology around the cleavage site regulate post-translational cleavage of the HIV-1 gp160 signal peptide

  1. Erik Lee Snapp
  2. Nicholas McCaul
  3. Matthias Quandte
  4. Zuzana Cabartova
  5. Ilja Bontjer
  6. Carolina Källgren
  7. IngMarie Nilsson
  8. Aafke Land
  9. Gunnar von Heijne
  10. Rogier W Sanders
  11. Ineke Braakman  Is a corresponding author
  1. Janelia Research Campus, United States
  2. Utrecht University, Netherlands
  3. dr heinekamp Benelux B.V., Netherlands
  4. National Institute of Public Health, Czech Republic
  5. Academic Medical Center, Netherlands
  6. Stockholm University, Sweden
  7. Stockholm Unversity, Sweden
  8. Institute of Life Sciences, Netherlands
Research Article
  • Cited 3
  • Views 1,615
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Cite this article as: eLife 2017;6:e26067 doi: 10.7554/eLife.26067

Abstract

Like all other secretory proteins, the HIV-1 envelope glycoprotein gp160, is targeted to the endoplasmic reticulum (ER) by its signal peptide during synthesis. Proper gp160 folding in the ER requires core glycosylation, disulfide-bond formation and proline isomerization. Signal-peptide cleavage occurs only late after gp160 chain termination and is dependent on folding of the soluble subunit gp120 to a near-native conformation. We here detail the mechanism by which co-translational signal-peptide cleavage is prevented. Conserved residues from the signal peptide and residues downstream of the canonical cleavage site form an extended alpha-helix in the ER membrane that covers the cleavage site, thus preventing cleavage. A point mutation in the signal peptide breaks the alpha helix allowing co-translational cleavage. We demonstrate that postponed cleavage of gp160 enhances functional folding of the molecule. The change to early cleavage results in decreased viral fitness compared to wild-type HIV.

Article and author information

Author details

  1. Erik Lee Snapp

    Janelia Research Campus, Ashburn, United States
    Competing interests
    Erik Lee Snapp, Has filed a patent application with and licensed technology to Lucigen Corp (U.S. Patent Application 15/152/908). The technology is not related to this manuscript..
  2. Nicholas McCaul

    Cellular Protein Chemistry, Utrecht University, Utrecht, Netherlands
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-7888-7815
  3. Matthias Quandte

    dr heinekamp Benelux B.V., Riethoven, Netherlands
    Competing interests
    No competing interests declared.
  4. Zuzana Cabartova

    National Reference Laboratory for Viral Hepatitis, National Institute of Public Health, Šrobárova, Czech Republic
    Competing interests
    No competing interests declared.
  5. Ilja Bontjer

    Department of Medical Microbiology, Academic Medical Center, Amsterdam, Netherlands
    Competing interests
    No competing interests declared.
  6. Carolina Källgren

    Department of Biochemistry and Biophysics, Stockholm University, Stockholm, Sweden
    Competing interests
    No competing interests declared.
  7. IngMarie Nilsson

    Department of Biochemistry and Biophysics, Stockholm Unversity, Stockholm, Sweden
    Competing interests
    No competing interests declared.
  8. Aafke Land

    Hogeschool Utrecht, Institute of Life Sciences, Utrecht, Netherlands
    Competing interests
    No competing interests declared.
  9. Gunnar von Heijne

    Department of Biochemistry and Biophysics, Stockholm University, Stockholm, Sweden
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-4490-8569
  10. Rogier W Sanders

    Department of Medical Microbiology, Academic Medical Center, Amsterdam, Netherlands
    Competing interests
    Rogier W Sanders, Is listed as an inventor on patents involving recombinant, soluble native-like Env trimers (EP2975053A1, EP2765138A3, WO/2017/055522A1, WO/2011/108937, WO/2010/041942, WO/2008/103428A2, WO/2003/022869A2). The technology is not related to this manuscript..
  11. Ineke Braakman

    Cellular Protein Chemistry, Utrecht University, Utrecht, Netherlands
    For correspondence
    i.braakman@uu.nl
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-1592-4364

Funding

Nederlandse Organisatie voor Wetenschappelijk Onderzoek

  • Nicholas McCaul
  • Matthias Quandte
  • Aafke Land
  • Ineke Braakman

Netherlands AIDS Fund

  • Aafke Land

Seventh Framework Programme (ITN 'Virus Entry')

  • Nicholas McCaul
  • Matthias Quandte
  • Ineke Braakman

National Institutes of Health (NIH AI-51519)

  • Erik Lee Snapp

Swedish Cancer Foundation

  • IngMarie Nilsson
  • Gunnar von Heijne

Knut and Alice Wallenberg Foundation

  • Gunnar von Heijne

European Research Council (ERC-StG-2011-280829-SHEV)

  • Rogier W Sanders

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: February 27, 2017
  2. Accepted: July 26, 2017
  3. Accepted Manuscript published: July 28, 2017 (version 1)
  4. Version of Record published: August 23, 2017 (version 2)

Copyright

© 2017, Snapp 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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