title: Domain III from class II fusion proteins functions as a dominant-negative inhibitor of virus membrane fusion.
abstract: 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.
authors.affiliation: Department of Cell Biology, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
authors.forename: Maofu
authors.initials: M
authors.lastname: Liao
authors.forename: Margaret
authors.initials: M
authors.lastname: Kielian
mesh_terms: D000524:Alphavirus / Q000378:metabolism*; D000818:Animals; D002478:Cells, Cultured; D004791:Enzyme Inhibitors / Q000737:chemistry*; D005416:Flavivirus / Q000378:metabolism*; D008561:Membrane Fusion / Q000187:drug effects*; D021962:Membrane Microdomains / Q000187:drug effects*; D008958:Models, Molecular; D017510:Protein Folding; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D014760:Viral Fusion Proteins / Q000378:metabolism* / Q000494:pharmacology*
chemical_list: D004791:Enzyme Inhibitors; D014760:Viral Fusion Proteins