@article{d48a0ea1f9844fe4a0c3c4b526a1b064,
title = "Structure and topology around the cleavage site regulate post-translational cleavage of the HIV-1 gp160 signal peptide",
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 cotranslational 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, which 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.",
keywords = "HIV-1, Cell line, HIV Envelope Protein gp160",
author = "Snapp, {Erik Lee} and Nicholas McCaul and Matthias Quandte and Zuzana Cabartova and Ilja Bontjer and Carolina K{\"a}llgren and Ingmarie Nilsson and Aafke Land and {Von Heijne}, Gunnar and Sanders, {Rogier W.} and Ineke Braakman",
note = "Funding Information: We thank Dr Manu Hegde (Cambridge, UK), Prof. Maarten Egmond (Utrecht University) and members of the Braakman lab for valuable discussions and suggestions. This work was supported by grants from the Netherlands Organization for Scientific Research (NWO)-Chemical Sciences (IBr, AL, NM), the Netherlands AIDS Fund (IBr, AL), the European Union 7th framework program, ITN {\textquoteleft}Virus Entry{\textquoteright} (IBr, MQ, NM), and by the Center for AIDS Research at the Albert Einstein College of Medicine and Montefiore Medical Center funded by the National Institutes of Health (NIH AI-51519) (ELS, ZC), the Swedish Cancer Foundation (CK, IMN, GvH), and the Knut and Alice Wallenberg Foundation (GvH). RWS is a recipient of a Vidi grant from NWO and a Starting Investigator Grant from the European Research Council (ERC-StG-2011–280829-SHEV). Publisher Copyright: {\textcopyright} Snapp et al.",
year = "2017",
month = jul,
day = "28",
doi = "10.7554/eLife.26067",
language = "English",
volume = "6",
journal = "eLife",
issn = "2050-084X",
publisher = "eLife Sciences Publications",
}
