Structure and topology around the cleavage site regulate post-translational cleavage of the HIV-1 gp160 signal peptide

Erik Lee Snapp, Nicholas McCaul, Matthias Quandte, Zuzana Cabartova, Ilja Bontjer, Carolina Källgren, Ingmarie Nilsson, Aafke Land, Gunnar Von Heijne, Rogier W. Sanders, Ineke Braakman

Research output: Contribution to journalArticlepeer-review

23 Citations (Scopus)

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.

Original languageEnglish
Article numbere26067
Number of pages25
JournaleLife
Volume6
DOIs
Publication statusPublished - 28 Jul 2017
Externally publishedYes

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