Binding Mechanism between CrkII and cAbl Kinase

Abstract

The interaction between non-receptor tyrosine kinase cAbl and signaling adaptor protein CrkII is implicated in diverse cellular processes, such as cell migration, proliferation, and bacterial infection. Because of the modular architecture of their structures, the interaction between cAbl and CrkII can undergo multiple alternative binding modes. This series of interactions starts with the binding of the N-terminal Src homology 3 (nSH3) domain of CrkII to proline-rich motifs (PRMs) in the intrinsically disordered region of cAbl kinase. Despite their importance, the detailed binding mechanism and functional significance of these interactions remains elusive. In this presentation, we report the detailed structure, thermodynamics, and kinetics of the interactions between the nSH3 domain of CrkII and PRMs of cAbl kinase. Our dynamics and structural studies, using NMR spectroscopy and crystallography, indicate that these modular interactions act as a binding catalyst that accelerates the association between CrkII and cAbl kinase. We also present our recent finding of a potent inhibitor of the cAbl-CrkII interaction.