Structural pliability adjacent to the kinase domain highlights contribution of FAK1 IDRs to cytoskeletal remodeling

Abstract

Therapeutic protein kinase inhibitors are designed on the basis of kinase structures. Here, we define intrinsically disordered regions (IDRs) in structurally hybrid kinases. We reveal that 65% of kinases have an IDR adjacent to their kinase domain (KD). These IDRs are evolutionarily more conserved than IDRs distant to KDs. Strikingly, 36 kinases have adjacent IDRs extending into their KDs, defining a unique structural and functional subset of the kinome. Functional network analysis of this subset of the kinome uncovered FAK1 as topologically the most connected hub kinase. We identify that KD-flanking IDR of FAK1 is more conserved and undergoes more post-translational modifications than other IDRs. It preferentially interacts with proteins regulating scaffolding and kinase activity, which contribute to cytoskeletal remodeling. In summary, spatially and evolutionarily conserved IDRs in kinases may influence their functions, which can be exploited for targeted therapies in diseases including those that involve aberrant cytoskeletal remodeling.

Data on evolution of intrinsically disordered regions of the human kinome and contribution of FAK1 IDRs to cytoskeletal remodeling

“…4C in Ref. [1]). Network of proteins involved in cellular migration is depicted with predicted inter-relationships.…”

“…Data reported here are related to the article entitled “Structural Pliability Adjacent to the Kinase Domain Highlights Contribution of FAK1 IDRs to Cytoskeletal Remodeling” [1]. Six figures and nine tables are presented in this article.…”

Galectin-1 inhibition attenuates profibrotic signaling in hypoxia-induced pulmonary fibrosis

“…18,19 Many of these activities are mediated by FAK1 (focal adhesion kinase-1), a non-receptor tyrosine kinase and a master regulator of cytoskeletal remodeling. 20,21 FAK1 has critical roles in fibroblast to myofibroblast differentiation. 22 Although elevated expression of activated/phosphorylated FAK1 (pFAK1) is often observed in the lungs of IPF patients, 23 the molecular mechanisms of FAK1 activation in pulmonary hypoxia remain unknown.…”