Journal
JOURNAL OF CELL BIOLOGY
Volume 171, Issue 1, Pages 111-120Publisher
ROCKEFELLER UNIV PRESS
DOI: 10.1083/jcb.200507075
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Funding
- NCI NIH HHS [P30-CA13330, P30 CA013330] Funding Source: Medline
- NIGMS NIH HHS [R01 GM052929, R01 GM52929] Funding Source: Medline
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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 A 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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