RT Journal Article SR Electronic T1 Intramolecular quality control: HIV-1 Envelope gp160 signal-peptide cleavage as a functional folding checkpoint JF bioRxiv FD Cold Spring Harbor Laboratory SP 2020.07.08.188672 DO 10.1101/2020.07.08.188672 A1 Nicholas McCaul A1 Matthias Quandte A1 Ilja Bontjer A1 Guus van Zadelhoff A1 Aafke Land A1 Rogier W. Sanders A1 Ineke Braakman YR 2020 UL http://biorxiv.org/content/early/2020/07/08/2020.07.08.188672.abstract AB The membrane-tethering signal peptides that target secretory proteins to the endoplasmic reticulum generally are assumed to be removed during translation, which is a prerequisite for proper folding. Cleavage of the HIV-1 gp120 signal peptide is late however and regulated by gp120 folding. While attached, a conserved cysteine in the signal peptide that is important for viral fitness, sustains disulfide isomerization during gp120 folding. Assembly of the N-terminal β-sandwich with a single C-terminal β-strand sets off signal-peptide cleavage, which releases gp120 from the membrane and from this disulfide-attacking cysteine and stabilizes the native gp120 fold. This is the first example of post-translational regulation of signal-peptide cleavage for intramolecular quality control of folding, with the signal peptide acting as a membrane-embedded propeptide with redox-active cysteine. Considering the ∼15% secretory proteins in our genome, and the frequency of N-C contacts in protein structures, this regulatory role of the signal peptide is bound to be a more common mechanism in secretory protein biosynthesis.Competing Interest StatementThe authors have declared no competing interest.