title: 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.
authors.affiliation: Morsani College of Medicine, Department of Pathology and Cell Biology, University of South Florida, Tampa, FL 33612, United States.
authors.forename: Jaymin J
authors.initials: JJ
authors.lastname: Kathiriya
authors.affiliation: Morsani College of Medicine, Department of Pathology and Cell Biology, University of South Florida, Tampa, FL 33612, United States.
authors.forename: Ravi Ramesh
authors.initials: RR
authors.lastname: Pathak
authors.affiliation: Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Alexandr
authors.initials: A
authors.lastname: Bezginov
authors.affiliation: Department of Cell Biology, Microbiology and Molecular Biology, University of South Florida, Tampa, FL 33620, United States.
authors.forename: Bin
authors.initials: B
authors.lastname: Xue
authors.affiliation: Department of Molecular Medicine, Morsani College of Medicine, University of South Florida, Tampa, FL 33612, United States; USF Health Byrd Alzheimer's Research Institute, University of South Florida, Tampa, FL 33612, United States; Laboratory of Structural Dynamics, Stability and Folding of Proteins, Institute of Cytology, Russian Academy of Sciences, St. Petersburg, Russian Federation.
authors.forename: Vladimir N
authors.initials: VN
authors.lastname: Uversky
authors.affiliation: Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Elisabeth R M
authors.initials: ERM
authors.lastname: Tillier
authors.affiliation: Morsani College of Medicine, Department of Pathology and Cell Biology, University of South Florida, Tampa, FL 33612, United States; Department of Cancer Biology and Evolution, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, United States. Electronic address: vdave@health.usf.edu.
authors.forename: Vrushank
authors.initials: V
authors.lastname: Davé
mesh_terms: D003599:Cytoskeleton / Q000201:enzymology / Q000378:metabolism*; D051417:Focal Adhesion Kinase 1 / Q000737:chemistry* / Q000378:metabolism; D064267:Intrinsically Disordered Proteins / Q000737:chemistry / Q000378:metabolism; D011487:Protein Conformation; D011499:Protein Processing, Post-Translational
chemical_list: D064267:Intrinsically Disordered Proteins; D051417:Focal Adhesion Kinase 1
keywords: Evolution of kinases; FAK1 signaling; Hub proteins; Intrinsic disorder in kinases; Network medicine; Protein-protein interaction networks