Multi-domain Proteins

plasminogen plasminogen

Conformational changes of multi-domain proteins, often triggered by changes in their inter-domain interactions, exert strong influence on their functions. In fibrinolysis, the conversion of plasminogen, consisting of seven domains, to its active form, plasmin, is accompanied by a closed-to-open conformational transition. While the individual domain structures of plasminogen have been determined with the aid of X-ray crystallography and NMR, 3D structures of entire plasminogen and plasmin and their conformational dynamics are not well understood. To gain insight into conformations of these proteins and dynamics relevant to conversion of plasminogen, we collaborate with the Llinás group and perform large-scale simulations. We are currently investigating specific bindings/interactions between domains in the closed conformation obtained from homology modeling and supra-fold of a fully extended structure. These inter-domain interactions are believed to play a key role in the dynamic conversion of the protein. Future directions include simulations of plasmin (and its variants) to obtain information about its open structure and activation pathways from its precursor plasminogen.

Further reading:

H. Kim, M. Y. Choi, H. J. Kim and M. Llinás, Conformational Dynamics and Ligand Binding in the Multi-Domain Protein PDC109, PLoS One 5(2): e9180 (2010).