Abstract
Focal adhesion kinase (FAK) is required for signaling in the heart. S910 phosphorylated FAK is known to cause pathological cardiac hypertrophy. The switching of FAK between its inactive (-i), activated (-a) and hyperactive (-h) state is controlled by phosphorylation. FAK consists of three domains, namely: FERM, Kinase, and FAT joined by linkers L1 and L2. The structural basis of FAK phosphorylation and signaling to the downstream pathways is not understood. In this work, we carried out homology modeling and domain assembly of full length human iFAK and aFAK. 100 ns classical molecular dynamic simulations were performed using AMBER14 and effect of S910 phosphorylation on FAK was investigated. The iFAK model superposed on a small angel X-ray scattering (SAXS) derived model with RMSD of 1.18 Å for 590 Cα atoms. aFAK showed S910 phosphorylation site in L2 shielded by FERM. S910 phosphorylation in hFAK led to its exposure accompanied by a large conformational change and exposing the previously buried Grb2 interaction site responsible for causing cardiac hypertrophy. The models of FAK are in agreement with diverse experimental data and observed differences in biological action. Understanding the structure activity relationships of FAK in response to phosphorylation is important for its future therapeutic modulation.
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