TY - JOUR TI - Structure and topology around the cleavage site regulate post-translational cleavage of the HIV-1 gp160 signal peptide AU - Snapp, Erik Lee AU - McCaul, Nicholas AU - Quandte, Matthias AU - Cabartova, Zuzana AU - Bontjer, Ilja AU - Källgren, Carolina AU - Nilsson, IngMarie AU - Land, Aafke AU - von Heijne, Gunnar AU - Sanders, Rogier W AU - Braakman, Ineke A2 - Gilmore, Reid VL - 6 PY - 2017 DA - 2017/07/28 SP - e26067 C1 - eLife 2017;6:e26067 DO - 10.7554/eLife.26067 UR - https://doi.org/10.7554/eLife.26067 AB - 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. KW - signal peptide KW - translocation KW - endoplasmic reticulum KW - HIV KW - gp160 KW - protein folding JF - eLife SN - 2050-084X PB - eLife Sciences Publications, Ltd ER -