PLoS Pathogens | |
Charge-Surrounded Pockets and Electrostatic Interactions with Small Ions Modulate the Activity of Retroviral Fusion Proteins | |
Daan M. F. van Aalten1  Alexander W. Schüttelkopf1  Daniel Lamb2  David W. Brighty2  | |
[1] Division of Molecular Microbiology, College of Life Sciences, University of Dundee, Dundee, United Kingdom;The Biomedical Research Institute, College of Medicine, Ninewells Hospital, The University of Dundee, Dundee, United Kingdom | |
关键词: HTLV-1; Membrane fusion; Crystal structure; Chlorides; Asparagine; Viral structure; Arginine; Electrostatics; | |
DOI : 10.1371/journal.ppat.1001268 | |
学科分类:生物科学(综合) | |
来源: Public Library of Science | |
【 摘 要 】
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.
【 授权许可】
CC BY
【 预 览 】
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RO201902012397719ZK.pdf | 5571KB | download |