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January 2009 - March 2010

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University of Minnesota Twin Cities
School of Dentistry
Division of Epidemiology and Community Health

PI: Wei Zhang

Structural Studies of Alphavirus Membrane Fusion in Situ

Alphaviruses, single-stranded RNA viruses within the Togaviridaefamily, are important human and animal pathogens. These viruses invade the host cells through the receptor-mediated endocytosis pathway. The acidic environment in the endosome induces fusion of the viral envelope and the endosomal membrane, allowing delivery of the viral genomic material into the cytoplasm of the infected cell. The energy cost for merging the hydrated membranes is endowed with the conformational changes and oligomeric rearrangements of the viral E1 glycoproteins, a class-II fusion protein. Although the crystal structures of the E1 ecto-domain in pre- and post-fusion conformations were determined, the structural details of the intermediate organizations of the fusion protein during the course of membrane fusion are poorly understood. Major obstacles that have impeded vigorous structural studies are the aggregation and heterogeneity of virus particles at low-pH, and additive heterogeneity introduced by non-uniform target membranes. This project employs several novel procedures to overcome such difficulties and produce eligible samples of alphavirus in complex with lipid membranes at acidic pH. Cryo-electron microscopy and three-dimensional image reconstruction techniques are used to determine the structure of the virus-membrane complex at nanometer resolution. Fitting the crystal structures of the E1 protein into the reconstruction map will lead to discovery of the conformation, oligomerization, and organization of E1 when it inserts into a target membrane upon acidification. The long-term objective of this research is to outline the detailed steps of viral protein conformational changes correlating with membrane remodeling and fusion. The experience obtained from this study can be generalized and applied to similar structural investigations that involve other small-enveloped viruses, such as Flaviviruses. Knowledge gained in this study will also be beneficial for the development of antiviral strategies.

Group Members

M. A. Arunagirinathan, Research Associate
Sheng Cao, Research Associate