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Mechanism of BVDV fusion (PESTIVIRUS FUSION)
Start date: 01 Sep 2007, End date: 31 Aug 2009 PROJECT  FINISHED 

Increasing evidence suggested that BVDV glycoprotein E2 belongs to the class II viral fusion proteins like flavivirus E and alphavirus E1 protein. In spite of further similarities in entry pathways of BVDV and flavi- and alphaviruses, recently a fundamental difference in the initiation of fusion process was reported.While flavi- and alphavirus fusion is initiated upon environmental acidification, BVD virions are stabilized by disulfide bridges in the viral glycoproteins. Reduction of these disulfide bridges during invasion facilitates the acid dependent fusion. For closely related Hepatitis C Virus also a considerable acid resistance was observed, suggesting a similar fusion mechanism.The mechanism of BVDV membrane fusion will be the main goal of this stud y. This requires substantial structural knowledge of the fusion protein. Thus structural analyses on pestiviral glycoproteins will be performed. Disulfide bridges in the E1-E2 heterodimer, purified from virions, will be mapped. In addition the crystal structure of E2 and/or the E1-E2 heterodimer, which is the predominant glycoprotein in the virion, will be determined from glycoproteins that are expressed in Drosophila cells.A cell-based fusion assay will be established to identify the pestiviral fusion protein by expression of pestiviral glycoproteins at the cell surface. Mutation analysis using reverse genetics will result in the identification of the fusion peptide Understanding of pestiviral fusion mechanism and knowledge of the 3D structure of the pestiviral glycoproteins will have a tremendous impact in understanding the molecular mechanisms of pestivirus entry, and of enveloped viruses in general.In particular, the differences to fusion mechanisms of flavi- and alphavirus promise an exciting new picture of the class II fusion protein structure/function relationship. The researcher as molecular virologist acquire methods of structural biology and thus strengthen his scientific independence and maturity.
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