Structure and topology around the cleavage site regulate post-translational cleavage of the HIV-1 gp160 signal peptide
- Janelia Research Campus, United States
- Utrecht University, Netherlands
- dr heinekamp Benelux B.V., Netherlands
- National Institute of Public Health, Czech Republic
- Academic Medical Center, Netherlands
- Stockholm University, Sweden
- Stockholm Unversity, Sweden
- Institute of Life Sciences, Netherlands
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.
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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.
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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Structure and topology around the cleavage site regulate post-translational cleavage of the HIV-1 gp160 signal peptide
eLife 6:e26067.
https://doi.org/10.7554/eLife.26067
