Structural pliability adjacent to the kinase domain highlights contribution of FAK1 IDRs to cytoskeletal remodeling
| Autor: | Vladimir N. Uversky, Elisabeth R. M. Tillier, Vrushank Davé, Jaymin J. Kathiriya, Ravi Ramesh Pathak, Bin Xue, Alexandr Bezginov |
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| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Network medicine 030102 biochemistry & molecular biology Protein Conformation Kinase Biophysics Therapeutic protein Biology Biochemistry Article Analytical Chemistry Cell biology Intrinsically Disordered Proteins Functional networks 03 medical and health sciences 030104 developmental biology Protein kinase domain Focal Adhesion Kinase 1 Kinome Kinase activity Cytoskeleton Protein Processing Post-Translational Molecular Biology |
| Zdroj: | Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics. 1865:43-54 |
| ISSN: | 1570-9639 |
| DOI: | 10.1016/j.bbapap.2016.10.002 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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