SummaryRemoval 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 well before translation termination, we here report two novel post-targeting functions for the HIV-1 gp120 signal peptide, which remains attached until gp120 folding triggers its removal. First, the signal peptide improves fidelity of folding by enhancing conformational plasticity of gp120 by driving disulfide isomerization through a redox-active cysteine, at the same time delaying folding by tethering the N-terminus to the membrane, which needs assembly with the C-terminus. Second, its carefully timed cleavage represents intramolecular quality control and ensures release and stabilization of (only) natively folded gp120. Postponed cleavage and the redox-active cysteine both are highly conserved and important for viral fitness. Considering the ∼15% secretory proteins in our genome and the frequency of N-to-C contacts in protein structures, these regulatory roles of the signal peptide are bound to be more common in secretory-protein biosynthesis.
Accelerated corrosion of marine-grade steel by a redox-active, cysteine-rich barnacle cement protein
