The plan is to perform protein purification and isolate higher order 500kDa protein complexes in vitro followed by hands on training experience of cryo-electron microscopy experiments.
The contact system is central to crosstalk between coagulation and inflammation and constitutes the unifying principle for diverse disorders including cancer, hereditary angiodema and cerebrovascular diseases such as alzheimers, stroke. Contact factors Factor XII, prekallikrein, are enzymes and co-factor kininogen utilise key protein modules to mediate binding interactions to cognate cell receptors and diverse ligands which regulate protease activation. Contact activation can trigger both plasma coagulation via the intrinsic pathway (via Factor XI) and inflammation via bradykinin release. Models of cardiovascular disease indicate it is a cooperation of the contact factors with endothelium, platelets and leukocytes that contributes to the pathways driving thrombosis. To advance this area we will study the molecular basis of how contact factors assemble on the different cell receptors from endothelial cells, leukocytes and platelets using a multidisciplinary approach. Our original hypothesis is that elucidating the structure of cognate cell receptors and co-factors regulating contact protein enzyme activation in inflammatory and plasma coagulation pathways will in the long term provide a scaffold to develop antagonists and therapies for diverse diseases.
The new technique made recently available for the project is Cryo-electron microscopy and the equipment for this project is a Titan Krios electron microscope together with a revolutionary Gatan K3 direct electron detector as part of the midlands cryo-EM facility. This complements existing techniques in the emsley lab by allowing the determination of protein structures to atomic resolution without the need to grow crystals and with smaller amounts of sample material. The long term goal is to determine the high resolution structure of macromolecule complexes and determine the organising principle underlying how co-factor proteins organise enzymes to efficiently cleave substrates.
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