Intramolecular quality control: HIV-1 envelope gp160 signal-peptide cleavage as a functional folding checkpoint

Nicholas McCaul, Matthias Quandte, Ilja Bontjer, Guus van Zadelhoff, Aafke Land, Ema T. Crooks, James M. Binley, Rogier W. Sanders, Ineke Braakman

Research output: Contribution to journalArticlepeer-review

5 Citations (Scopus)


Removal of the membrane-tethering signal peptides that target secretory proteins to the endoplasmic reticulum is a prerequisite for proper folding. While generally thought to be removed co-translationally, we report two additional post-targeting functions for the HIV-1 gp120 signal peptide, which remains attached until gp120 folding triggers its removal. First, the signal peptide improves folding fidelity by enhancing conformational plasticity of gp120 by driving disulfide isomerization through a redox-active cysteine. Simultaneously, the signal peptide delays folding by tethering the N terminus to the membrane, until assembly with the C terminus. Second, its carefully timed cleavage represents intramolecular quality control and ensures release of (only) natively folded gp120. Postponed cleavage and the redox-active cysteine are both highly conserved and important for viral fitness. Considering the ∼15% proteins with signal peptides and the frequency of N-to-C contacts in protein structures, these regulatory roles of signal peptides are bound to be more common in secretory-protein biogenesis.

Original languageEnglish
Article number109646
Number of pages21
JournalCell Reports
Issue number9
Early online date31 Aug 2021
Publication statusPublished - 31 Aug 2021
Externally publishedYes


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