The pre‐transmembrane region of the human immunodeficiency virus type‐1 glycoprotein: a novel fusogenic sequence

Abstract

We have investigated membrane interactions and perturbations induced by NH(2)-DKWASLWNWFNITNWLWYIK-COOH (HIV(c)), representing the membrane interface-partitioning region that precedes the transmembrane anchor of the human immunodeficiency virus type-1 gp41 fusion protein. The HIV(c) peptide bound with high affinity to electrically neutral vesicles composed of dioleoylphosphatidylcholine, dioleoylphosphatidylethanolamine and cholesterol (molar ratio, 1:1:1), and induced vesicle leakage and lipid mixing. Infrared spectra suggest that these effects were promoted by membrane-associated peptides adopting an alpha-helical conformation. A sequence representing a defective gp41 phenotype unable to mediate both cell-cell fusion and virus entry, was equally unable to induce vesicle fusion, and adopted a non-helical conformation in the membrane. We conclude that membrane perturbation and adoption of the alpha-helical conformation by this gp41 region might be functionally meaningful.

The Aromatic Domain of the Coronavirus Class I Viral Fusion Protein Induces Membrane Permeabilization: Putative Role during Viral Entry

“…This region is proximal to a predicted TM domain (Figure 2A), which was identified using the WW octanol hydrophobicity scale that allows for the identification of TM helices of membrane proteins with very high accuracy (73). On the basis of these observations, it is unlikely that the aromatic domain is part of the TM anchor as previously predicted by Rota et al (6), rather, as described for the aromatic domains of HIV-1 and EboV (10,55,56,58), this region is most likely an independent domain proximal to the TM anchor of the S2 subunit.…”

“…Nieva and colleagues have shown that, for HIV-1 and EboV, this large region of high interfacial hydrophobicity is segmented into two independent domains: one aromatic amino acid rich segment at the C-terminal portion of this domain and an adjacent segment comprising the TM anchor of the fusion protein (10,55,56). The separation of this large region into two distinct domains is consistent with the observation that the C-terminal hydrophobic domains of these viral fusion proteins are considerably longer (35-40 amino acids) than the ∼20 amino acids required for a single R helix to span a membrane.…”

“…The resulting structure is believed to align the fusion peptide, aromatic domain, and TM anchor (30), resulting in viral/ cell membrane fusion. On the basis of the observations that (1) the aromatic peptides of coronaviruses and other viruses (10,55,56,58) strongly interact with and disrupt membranes and (2) the overall conservation of these sequences in many viruses, we hypothesize that the aromatic domain of class I viral fusion proteins plays a critical role in viral/cell membrane fusion. Specifically, we propose that the aromatic domain, in conjunction with the fusion peptide and the TM anchor, forms a continuous track of hydrophobic, membraneinteracting surfaces that provide a low-energy (low-barrier) path for lipid flow and membrane fusion during virion/cell fusion ( Figure 7).…”

“…This region of aromatic amino acids, according to the trimer-of-hairpins model, would also align with the fusion peptide and TM domain during apposition of the target cell and viral membranes and thus could add to the overall hydrophobicity of the environment and contribute to the distortion of the lipid membranes necessary for fusion. Using synthetic peptides analogous to the aromatic domains of HIV-1 gp41 and EboV glycoprotein 2 (GP2), Nieva and colleagues have shown that these aromatic regions partition into and perturb the integrity of lipid vesicles (10,55,56). Not surprisingly, proximal to the TM domain of the CoV S protein, there is a similar region enriched in aromatic amino acids, which is extraordinarily conserved throughout the CoronaViridae and lies in an identical location to the aromatic domains of HIV (Figures 1 and 2) and EboV ( Figure 2).…”

Aromatic residues at the edge of the antibody combining site facilitate viral glycoprotein recognition through membrane interactions

“…Shortly thereafter, Suarez et al (18) reported on the ability of MPER peptides to associate with, permeabilize, and induce fusion between membranes. Since then, a number of membraneassociated MPER peptide structures have been resolved using NMR spectroscopy methods (19)(20)(21).…”