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Published 10 October 2005. doi:10.1083/jcb.200507075
The Rockefeller University Press, 0021-9525 $8.00
JCB, Volume 171, Number 1, 111-120
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Article

Domain III from class II fusion proteins functions as a dominant-negative inhibitor of virus membrane fusion



Maofu Liao and Margaret Kielian

Department of Cell Biology, Albert Einstein College of Medicine, Bronx, NY 10461

Correspondence to Margaret Kielian: kielian{at}aecom.yu.edu

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.

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.


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