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Comparative structural analysis of retroviral fusion proteins identifies regions that modulate membrane fusion: a potential retroviral achilles heal?
Retrovirology volume 8, Article number: A163 (2011)
Refolding of viral class-1 membrane fusion proteins from a native state to a trimer-of-hairpins structure promotes entry of viruses into cells. Here we present the structure of the bovine leukaemia virus transmembrane glycoprotein (TM) and identify a group of asparagine residues at the membrane-distal end of the trimer of hairpins that is strikingly conserved among divergent viruses. These asparagines are not essential for surface display of pre-fusogenic envelope. Instead, substitution of these residues dramatically disrupts membrane fusion. Our data indicate that through electrostatic interactions with of a chloride ion the asparagine residues promote assembly and profoundly stabilize the fusion-active structures that are required for viral envelope-mediated membrane fusion. Moreover, the BLV TM structure also reveals a charge-surrounded hydrophobic pocket on the central coiled coil and interactions with basic residues that cluster around this pocket are critical to membrane fusion and form a target for peptide inhibitors of envelope function. Charge-surrounded pockets and electrostatic interactions with small ions are common leitmotifs among class-1 fusion proteins. We will discuss the impact of these observations in light of current models of membrane fusion and as potential targets for therapeutic inhibition of viral entry.
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Open Access This article is published under license to BioMed Central Ltd. This is an Open Access article is distributed under the terms of the Creative Commons Attribution License ( https://creativecommons.org/licenses/by/2.0 ), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
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Lamb, D., Schüttelkopf, A.W., van Aalten, D.M.F. et al. Comparative structural analysis of retroviral fusion proteins identifies regions that modulate membrane fusion: a potential retroviral achilles heal?. Retrovirology 8 (Suppl 1), A163 (2011). https://doi.org/10.1186/1742-4690-8-S1-A163
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DOI: https://doi.org/10.1186/1742-4690-8-S1-A163
Keywords
- Fusion Protein
- Asparagine
- Membrane Fusion
- Peptide Inhibitor
- Bovine Leukaemia Virus