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Biophysical Investigation of the Intermediate Steps of Flavivirus Membane Fusion

Grant number: 08/01636-8
Support type:Scholarships in Brazil - Post-Doctorate
Effective date (Start): July 01, 2008
Effective date (End): June 30, 2010
Field of knowledge:Biological Sciences - Biophysics - Molecular Biophysics
Principal researcher:Paolo Marinho de Andrade Zanotto
Grantee:Ana Vitória Botelho
Home Institution: Laboratório Nacional de Luz Síncrotron (LNLS). Centro Nacional de Pesquisa em Energia e Materiais (CNPEM). Ministério da Ciência, Tecnologia e Inovações (Brasil). Campinas , SP, Brazil

Abstract

Dengue virus is a member of the Flaviviridae family, genus flavivirus, and constitutes one of the most serious emerging viruses. Protein E is the major surface protein of the viral envelope and is responsible for the entry of the virus in the host cell. Virus entry occurs through the binding of protein E (envelope) to specific receptors. In this step, protein E is found as dimer positioned flat in an anti-parallel arrangement on the viral surface. After binding, the virus enters cells by receptor-mediated endocytosis inducing conformational changes in the protein, going from dimer to monomers. In the monomer form, protein E exposes its fusion loops, inserting them into the cellular membrane promoting a subsequent trimer formation, which catalyzes membrane fusion of the virus with the host cell. This fusion process creates a fusion pore, through which the virus genome is delivered into the cytoplasm of the host cell, leading to subsequent infection. The present project aims to investigate the mechanisms involved in the conformational changes of the fusion protein E, to better understand the mechanistic details associated with the fusion steps of flaviviruses. This project is based on examining the conformational changes and the oligomeric states of the E protein by thermodynamic and kinetic analysis, using as model systems the ectodomains sE, as well as the integral protein E. In addition, full-length E will be expressed and inserted into liposomes to correlate the kinetics of membrane fusion with lipid identity. This work presents experiments to deepen our understanding in the functions of the Type II fusion proteins, with repercussions for basic science as well as eventual assay development for drug discovery against Dengue and related flaviviruses.

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