STRUCTURES OF ALPHAVIRUS SPIKES AND RECEPTORS

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The Alphavirus is one genera of the Togaviridae family. Because of their broad tissue specificity, these enveloped RNA viruses can cause a wide variety of serious syndromes; encephalitis, myocarditis, myalgias, tendonitis, arthritis, and leukopenia. It has been clearly shown that at low pH the envelope glycoprotein spikes undergo large conformational changes, and these conformational changes represent early events in the membrane fusion process. In addition, mutational analysis has shown that changes in a few residues in the spike proteins can alter membrane penetration rates and neurovirulence. Antigenic epitopes have been determined on many of these spike proteins, and some have been found to overlap the cell receptor binding region. These and other studies have clearly defined important aspects of the spike proteins but structural information is needed to better understand the mechanisms of alphavirus infection and antibody mediated neutralization. We plan to examine several of the alphaviruses (Sindbis, Semliki Forest, and Ross River) and their various altered states using a combination of X- ray crystallography and electron microscopy. We will use crystallography to determine the structures of the spike proteins, immune complexes of these spike proteins, and the cellular receptors. Since a great number of important sites have already been mapped using mutagenesis experiments, these structures will yield a great deal of information as to the processes of neurovirulence, membrane fusion, and antibody mediated neutralization. These structures will also be used in the context of electron microscopy images to interpret the low resolution structures of larger species which cannot be examined using crystallographic means such as virus/receptor complexes, virus/antibody complexes, and membrane fusion precursors.