"Movement is a defining characteristic of life at the sub-cellular level. Dynein is one of the motor proteins that power this movement. It carries a wide range of cargos and dynein dysfunction has been implicated in many human diseases. Unlike other motors only one cytoplasmic dynein exists which suggests that it has unique mechanisms for controlling specificity i.e. how it carries cargo to the right place at the right time. In order to understand these mechanisms detailed structural knowledge of the cargo interacting dynein tail will be essential.
We propose to study the structure dynein tail by achieving three independent objectives. 1) Obtain the crystal structure of the yeast dynein tail. To do this we will combine a plasmid based S. cerevisiae expression system developed at our institute with advanced fermentation techniques. 2) Recombinantly express mammalian dynein tail complexes for single particle electron microscopic analysis and biochemical characterization. This will be achieved using novel molecular biological techniques for expressing protein complexes combined with cryo-EM. 3) Analysis of viral interactions with dynein. This will be achieved by reconstituting dynein/virus movement in vitro and subsequently analyzing dynein/virus complexes by EM tomography.
Together these approaches will allow us to analyze the structure and function of the whole dynein tail complex to gain insight in dynein/cargo specificity for the first time. This innovative project will significantly strengthen European science by serving as an excellent starting point for many new and groundbreaking lines of research. Furthermore, it will allow the applicant move to a different European country as well as switch fields of research."
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