Abstract
Dynamics of proteins plays critical roles for functions and interactions. Traditional structural biology provides limited insights on highly flexible, yet functional, regions, since these are absent in most crystal- and cryo-EM structures. This project will utilize an approach that combines molecular biology, NMR spectroscopy, and molecular dynamics simulations to characterise how dynamic proteins interact with binding partners. Focus will be on two blood coagulation factors: von Willebrand factor and factor VIII, where the disordered a3 domain of factor VIII is imperative for high-affinity binding. This project is highly interdisciplinary, involving substantial elements of computational modelling, NMR spectroscopy and wet-lab work.
References
1 T.A. Springer “von Willebrand factor, Jedi knight of the bloodstream” Blood, 124, (2014): 1412-1425
2 N. Shiltagh, J. Kirkpatrick, L.D. Cabrita, T.A.J. Mckinnon, K. Thalassinos, E.G.D. Tuddenham, and D.F. Hansen. “Solution structure of the major factor VIII binding region on von Willebrand factor.” Blood 123, (2014): 4143-4151.
3 A. Kuzmanic, R.B. Pritchard, D.F. Hansen, F.L. Gervasio, J. Phys. Chem. Lett. 10, (2019): 1928-1934
4 L. Andersen, K. S. Troelsen, G. Bolt, L. Thim, B. Wu, X. Zhao, E.G.D. Tuddenham, T.E. Nielsen, D.A. Tanner, J.H. Faber, J. Breinholt, J.E. Rasmussen, D.F. Hansen “Interaction between the a3 domain of Factor VIII and the TIL’E’ domains of the von Willebrand Factor” Biophysical Journal, under review (2019)
5 A. Yee, A.N. Oleskie, A.M. Dosey, C.A. Kretz, R.D. Gildersleeve, S. Dutta, M. Su, D. Ginsburg, and G. Skiniotis.. “Visualization of an N-terminal fragment of von Willebrand factor in complex with factor VIII”. Blood. 126, (2015): 939–42