Rotavirus is the major cause of several, life-threatening gastroenteritis in young children and animals. Rotaviruses are large (1000 A), complex, icosahedral assemblies. This virus has been the subject of extensive biochemical, genetic and structural studies because of its medical relevance, intriguing structural complexity, and unique strategies of morphogenesis and replication. Rotaviruses contain 11 segments of double- stranded RNA encapsulated within three concentric capsid layers. Of the 11 proteins encoded by the genome, six are structural (VP1, VP2, VP3, VP4, VP6 and VP7) and five are non-structural (NSP1-5). In the last three years, they have made exciting new discoveries that have provided a better characterization of the rotavirus, structure and a deeper insight into the structural basis of various virus functions such as trypsin-enhanced infectivity, virus assembly and endogenous transcription. These recent developments, together with other developments in the molecular biology of rotaviruses and related systems, have allowed plans for more in-depth dissection of structure-function correlations in rotavirus using high resolution electron cryomicroscopy together with computer image reconstruction techniques and X-ray crystallographic information. The specific objectives of the proposed project are: 1) To further investigate the structural basis of protease-enhanced infectivity in rotavirus, and localize the various functional domains in the VP4 spike structure using monoclonal antibodies and recombinant virus-like particles. 2) To further understanding of the structural basis of endogenous transcription in rotavirus. 3) To carry out higher resolution structural characterization of rotavirus to understand protein-protein interactions that modulate various functions of the virus. 4) To carry out structural analysis of NSP4, an intracellular receptor, and study its interaction with VP6, and viral cell attachment protein VP4.
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