INFLUENZA HEMAGGLUTININ IS SPRING-LOADED BY A METASTABLE NATIVE CONFORMATION

Enveloped viruses enter cells by protein-mediated membrane fusion. For influenza virus, membrane fusion is regulated by the conformational s tate of the hemagglutinin (HA) protein, which switches from a native ( nonfusogenic) structure to a fusion-active (fusogenic) conformation wh en exposed to the acidic environment of the cellular endosome. Here we demonstrate that destabilization of HA at neutral pH, with either hea t or the denaturant urea, triggers a conformational change that is bio chemically indistinguishable from the change triggered by low pH. In e ach case, the conformational change is coincident with induction of me mbrane-fusion activity, providing strong evidence that the fusogenic s tructure is formed, These results indicate that the native structure o f HA is trapped in a metastable state and that the fusogenic conformat ion is released by destabilization of native structure. This strategy may be shared by other enveloped viruses, including those. that enter the cell at neutral pH, and could have implications for understanding the membrane fusion step of HIV infection.