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

• Published in: eLife Vol. 6
• Main Authors: Snapp, Erik Lee, McCaul, Nicholas, Quandte, Matthias, Cabartova, Zuzana, Bontjer, Ilja, Källgren, Carolina, Nilsson, IngMarie, Land, Aafke, von Heijne, Gunnar, Sanders, Rogier W, Braakman, Ineke
• Format: Journal Article
• Language: English
• Published: England eLife Science Publications, Ltd 28.07.2017; eLife Sciences Publications Ltd; eLife Sciences Publications, Ltd
• Subjects: Amino acids; Biochemistry and Chemical Biology; Cell Biology; Cell Line; Chemical bonds; Conformation; Endoplasmic reticulum; Gene mutation; Glycoprotein gp120; Glycoprotein gp160; Glycosylation; gp160; HIV; HIV Envelope Protein gp160 - chemistry; HIV Envelope Protein gp160 - metabolism; HIV-1 - physiology; Human immunodeficiency virus; Humans; Influenza; Isomerization; Laboratories; Peptides; Point mutation; Post-translation; Proline; Proteases; Protection and preservation; Protein Conformation; Protein Folding; Protein Sorting Signals; Protein structure; Protein Transport; Proteins; Proteolysis; Reproductive fitness; signal peptide; Structure (Literature); Translation; Translations; translocation; signal peptide; cell biology; translocation; HIV; biochemistry; protein folding; gp160; human; endoplasmic reticulum
• ISSN: 2050-084X; 2050-084X
• DOI: 10.7554/eLife.26067

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.