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Molecular basis of Tousled-Like Kinase 2 activation
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Molecular basis of Tousled-Like Kinase 2 activation
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Journal Article
Molecular basis of Tousled-Like Kinase 2 activation
2018
Overview
Tousled-like kinases (TLKs) are required for genome stability and normal development in numerous organisms and have been implicated in breast cancer and intellectual disability. In humans, the similar TLK1 and TLK2 interact with each other and TLK activity enhances ASF1 histone binding and is inhibited by the DNA damage response, although the molecular mechanisms of TLK regulation remain unclear. Here we describe the crystal structure of the TLK2 kinase domain. We show that the coiled-coil domains mediate dimerization and are essential for activation through ordered autophosphorylation that promotes higher order oligomers that locally increase TLK2 activity. We show that TLK2 mutations involved in intellectual disability impair kinase activity, and the docking of several small-molecule inhibitors of TLK activity suggest that the crystal structure will be useful for guiding the rationale design of new inhibition strategies. Together our results provide insights into the structure and molecular regulation of the TLKs.
The Tousled-like kinase (TLKs) family belongs to a distinct branch of Ser/Thr kinases that exhibit the highest levels of activity during DNA replication. Here the authors present the crystal structure of the kinase domain from human TLK2 and propose an activation model for TLK2 based on biochemical and phosphoproteomics experiments.
Publisher
Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
Subject
/ 631/57
/ 82/80
/ 82/83
/ Adenosine Triphosphate - analogs & derivatives
/ Adenosine Triphosphate - chemistry
/ Adenosine Triphosphate - metabolism
/ DNA
/ Docking
/ Escherichia coli - metabolism
/ Genetic Vectors - metabolism
/ Genomes
/ Humanities and Social Sciences
/ Humans
/ Intellectual Disability - enzymology
/ Intellectual Disability - genetics
/ Intellectual Disability - physiopathology
/ Kinases
/ Kinetics
/ Molecular Docking Simulation
/ Mutation
/ Protein Conformation, alpha-Helical
/ Protein Conformation, beta-Strand
/ Protein Interaction Domains and Motifs
/ Protein Kinase Inhibitors - chemistry
/ Protein Kinases - metabolism
/ Recombinant Proteins - chemistry
/ Recombinant Proteins - genetics
/ Recombinant Proteins - metabolism
/ Science
