Examination of focal adhesion kinase’s FAT domain structural response to applied mechanical load

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Alotaibi, Talal Eid

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Focal adhesion kinase (FAK) is a non-receptor tyrosine kinase. Activated FAK is crucial to many biological processes, such as cell proliferation, migration, and survival, all of which have been implicated in the progression and development of cancer. Tyrosine 925 is a Src-phosphorylation site that is located within the FAT domain in the C-terminal of FAK. It has been suggested that the helix containing Y925 (Helix 1) has to come out of the FAT bundle and the region flanking Y925 has to adopt β-strand conformation. In order to phosphorylate, the mechanisms promoting the required structural changes are unclear. So, Molecular Dynamics (MD) and Constant Force Molecular Dynamics (CFMD) simulations were used to study what makes Y925 accessible for phosphorylation. Under thermal fluctuation only and in the presence or the absence of LD motifs, MD simulations suggest that H1 does not appear to have a propensity to leave the bundle adopt β-strand conformation. Then, two different load scenarios were used; axial and perpendicular with 100 pN constant load applied to H1 N-terminus with the two paxillin LD motifs constrained. For both load scenarios, H1 has two different behaviors: typical and atypical. In the axial load scenario, the first two residues at the N-terminal of H1 (besides Y925) have low propensity to unfold. However, H1 does not show any proclivity to leave the bundle. For the perpendicular load scenario with the absence of P2 (LD motif binds to H1/H4 hydrophobic patch), one simulation out of 21 showed that H1 undergoes the required structural rearrangement. In general, CFMD simulations show that the FAT domain has a very low propensity (3%) to undergo the structural changes needed for Y925 phosphorylation. This has two implications: either mechanical load is insufficient to make Y925 available for phosphorylation and/or this kind of process (structural changes needed for Y925 phosphorylation) is slow process that needs a long time to occur.



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