Structure and topology around the cleavage site regulate post-translational cleavage of the HIV-1 gp160 signal peptide.
JSON
Snapp EL, McCaul N, Quandte M, Cabartova Z, Bontjer I, Källgren C, Nilsson I, Land A, von Heijne G, Sanders RW, Braakman I
Elife 6 (-) - [2017-07-28; online 2017-07-28]
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, 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.
PubMed 28753126
DOI 10.7554/eLife.26067
Crossref 10.7554/eLife.26067
pmc: PMC5577925
pii: 26067