Structural studies on viral receptor-binding proteins

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http://urn.fi/URN:ISBN:978-952-10-8262-7
Title: Structural studies on viral receptor-binding proteins
Author: Manole, Violeta
Contributor: University of Helsinki, Faculty of Biological and Environmental Sciences, Department of Biosciences
Institute of Biotechnology
Publisher: Helsingin yliopisto
Date: 2012-09-28
Language: en
URI: http://urn.fi/URN:ISBN:978-952-10-8262-7
http://hdl.handle.net/10138/36701
Thesis level: Doctoral dissertation (article-based)
Abstract: Structure. Almost everything around us has it. But why? What is it needed for? Since the early days of human enquiry people have tried to understand how things come together and stay assembled. As scientific discovery advanced, researchers from all fields of science have been at some point or another puzzled by problems related to structure. Among them, biologists discovered that there is more to the natural world surrounding us than meets the eye. Structural biology studies are often hypothesis-driven and require flexible methods to address specific questions on the relationship between structure and biological function. My thesis discusses three cases in which structure is fundamental to function, and presents three different approaches to solving the three-dimensional structure of entire viruses or virus proteins, going from relatively well-ordered systems to increasing heterogeneous ones. The first study is the characterization of African horsesickness virus, a double-stranded RNA icosahedrally-symmetric virus causing a severe disease in horses. I used electron cryo-microscopy and icosahedral reconstruction to determine the virion structures of two serotypes to 11 and 14 Å resolution. The three-dimensional structure allowed us to map two domains of the receptor-binding protein VP2, an important step for the informed design of new subunit vaccines for African horsesickness virus. The second study is a description of the spike complex of bacteriophage PRD1, a membrane-containing virus. Here, the major problem was to determine the organization of flexible, low abundance proteins involved in cell recognition and attachment. This sort of heterogeneity in biological systems is key to their function, but very unfavourable for structural analysis. We used a combination of different mutants, electron cryo-microscopy three-dimensional image reconstruction and atomic modeling to address the symmetry mismatch between the icosahedrally-symmetric capsid and the spike complex situated at the five-fold vertices and determined the architecture of the spike complex formed by protein P5 and the receptor-binding protein P2. The third study is a comparative biological and structural study of seven recently isolated pleomorphic viruses, which infect extremely halophilic archaea. I established the pleomorphic nature of this novel virion type by electron cryo-tomography. Detailed analysis using subtomographic processing showed the radial distribution of the membrane and the spike protein VP4, and led to an average structure of VP4.Ei saatavilla
Subject: structural biology
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