Charge-surrounded pockets and electrostatic interactions with small ions modulate the activity of retroviral fusion proteins

Daniel Lamb, Alexander W. Schuettelkopf, Daan M. F. van Aalten, David W. Brighty (Lead / Corresponding author)

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    Abstract

    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 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 among class-1 fusion proteins, suggesting that small molecules that specifically target such motifs should prevent assembly of the trimer-of-hairpins and be of value as therapeutic inhibitors of viral entry.

    Original languageEnglish
    Article numbere1001268
    Pages (from-to)-
    Number of pages12
    JournalPLoS Pathogens
    Volume7
    Issue number2
    DOIs
    Publication statusPublished - Feb 2011

    Keywords

    • T-CELL LEUKEMIA
    • VIRAL MEMBRANE-FUSION
    • MALTOSE-BINDING PROTEIN
    • COILED-COIL DOMAIN
    • VIRUS TYPE-I
    • IMMUNODEFICIENCY-VIRUS
    • ENVELOPE GLYCOPROTEIN
    • CRYSTAL-STRUCTURE
    • EBOLA-VIRUS
    • TRANSMEMBRANE GLYCOPROTEIN

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