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

Abstract

<jats:title>Summary</jats:title><jats:p>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.</jats:p>

Lassa virus glycoprotein complex review: insights into its unique fusion machinery

“…Conventional signal peptides are 18 to 30 amino acid peptides and are responsible for directing proteins to the proper intra-and/or extracellular location (203)(204)(205)(206)(207). After successful translocation, the signaling peptide is cleaved and degraded.…”

Molecular adaptations during viral epidemics

“…Host polymorphisms, especially variability in APOBEC3H as mentioned above (Ooms et al , 2013); stochasticity associated with population bottlenecks and genetic drift (Theys et al , 2018); and the heterogeneity of the host response associated with disease progression itself result in pronounced heterogeneity among the mutational landscapes within individual hosts. Despite these complicating factors, conserved features have emerged including specific amino acid replacements in the HIV‐1 reverse transcriptase (Larder & Kemp, 1989; Shafer et al , 2007) and Env proteins (Borrow et al , 1997; Van Duyne et al , 2019; McCaul et al , 2021), which confer drug resistance. The recent discovery of a highly divergent and highly virulent HIV‐1 variant, which likely emerged in the 1990s as a result of de novo mutation, in contrast to recombination (Wymant et al , 2022), emphasizes the vast mutational repertoire accessible to this virus.…”