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Elife. 2014 Dec 5;3:e04389. doi: 10.7554/eLife.04389.

Sequential conformational rearrangements in flavivirus membrane fusion.

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Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, United States.


The West Nile Virus (WNV) envelope protein, E, promotes membrane fusion during viral cell entry by undergoing a low-pH triggered conformational reorganization. We have examined the mechanism of WNV fusion and sought evidence for potential intermediates during the conformational transition by following hemifusion of WNV virus-like particles (VLPs) in a single particle format. We have introduced specific mutations into E, to relate their influence on fusion kinetics to structural features of the protein. At the level of individual E subunits, trimer formation and membrane engagement of the threefold clustered fusion loops are rate-limiting. Hemifusion requires at least two adjacent trimers. Simulation of the kinetics indicates that availability of competent monomers within the contact zone between virus and target membrane makes trimerization a bottleneck in hemifusion. We discuss the implications of the model we have derived for mechanisms of membrane fusion in other contexts.


West Nile virus; biophysics; conformational change; flavivirus; kinetics; membrane fusion; single particle; structural biology; viruses

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