Alphaviruses and flaviviruses infect cells through low pH-dependent membrane fusion reactions mediated by their structurally similar viral fusion proteins. During fusion, these class II viral fusion proteins trimerize and refold to form hairpin-like structures, with the domain III and stem regions folded back toward the target membrane-inserted fusion peptides. We demonstrate that exogenous domain III can function as a dominant-negative inhibitor of alphavirus and flavivirus membrane fusion and infection. Domain III binds stably to the fusion protein, thus preventing the foldback reaction and blocking the lipid mixing step of fusion. Our data reveal the existence of a relatively long-lived core trimer intermediate with which domain III interacts to initiate membrane fusion. These novel inhibitors of the class II fusion proteins show cross-inhibition within the virus genus and suggest that the domain III–core trimer interaction can serve as a new target for the development of antiviral reagents.
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10 October 2005
Article|
October 10 2005
Domain III from class II fusion proteins functions as a dominant-negative inhibitor of virus membrane fusion
Maofu Liao,
Maofu Liao
Department of Cell Biology, Albert Einstein College of Medicine, Bronx, NY 10461
Search for other works by this author on:
Margaret Kielian
Margaret Kielian
Department of Cell Biology, Albert Einstein College of Medicine, Bronx, NY 10461
Search for other works by this author on:
Maofu Liao
Department of Cell Biology, Albert Einstein College of Medicine, Bronx, NY 10461
Margaret Kielian
Department of Cell Biology, Albert Einstein College of Medicine, Bronx, NY 10461
Correspondence to Margaret Kielian: [email protected]
Abbreviations used in this paper: DV, dengue virus; Ex/M, excimer to monomer peak ratio; FIA, fusion-infection assay; HT, homotrimer; SFV, Semliki Forest virus; SIN, Sindbis virus; TBE, tick-borne encephalitis virus; TM, transmembrane; VSV, vesicular stomatitis virus.
Received:
July 18 2005
Accepted:
September 02 2005
Online ISSN: 1540-8140
Print ISSN: 0021-9525
The Rockefeller University Press
2005
J Cell Biol (2005) 171 (1): 111–120.
Article history
Received:
July 18 2005
Accepted:
September 02 2005
Citation
Maofu Liao, Margaret Kielian; Domain III from class II fusion proteins functions as a dominant-negative inhibitor of virus membrane fusion . J Cell Biol 10 October 2005; 171 (1): 111–120. doi: https://doi.org/10.1083/jcb.200507075
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