Regulation in cells and organisms is achieved by the interplay of proteins acting in concert to achieve a tight control over time and space. In the development of my research line, I focus on the molecular mechanisms of recognition and regulation that underlie biological processes, such as the arrest of bleeding and the innate immune defence against invading pathogens. The proteins involved are, typically, large multi-domain proteins that function in large complexes that collectively carry out elementary functions such as initiation, amplification, localization and inhibition. Activation of these proteins is likely determined by structural rearrangements within these multi-domain proteins and complexes. With protein crystallography we can study distinct states, e.g. activated vs. inactivated, of these large proteins at high spatial resolution.
However, this technique cannot provide the dynamical data that are required to arrive at comprehensive models of protein activation in these regulatory pathways. Therefore, I propose to train myself in single-molecule fluorescence (in particular the recent method of single-pair FRET), which is most applicable for studying the dynamics of large bio-molecules. The laboratories of profs Brunger and Chuat Stanford University (USA) provide an excellent environment for training in these structure-dynamics techniques. The proposed training research period enables me to technically widen and scientifically deepen my current research in the molecular mechanisms in haematology and immunology. The combination of structural and dynamical studies of medically important proteins will be a key element to the future attractiveness and competitiveness of my research group.
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