2. Academic Validation
  3. Molecular basis of Tousled-Like Kinase 2 activation

Molecular basis of Tousled-Like Kinase 2 activation

  • Nat Commun. 2018 Jun 28;9(1):2535. doi: 10.1038/s41467-018-04941-y.
Gulnahar B Mortuza 1,  Dario Hermida 1,  Anna-Kathrine Pedersen 2,  Sandra Segura-Bayona 3,  Blanca López-Méndez 4,  Pilar Redondo 5,  Patrick Rüther 2,  Irina Pozdnyakova 4,  Ana M Garrote 5,  Inés G Muñoz 5,  Marina Villamor-Payà 3,  Cristina Jauset 3,  Jesper V Olsen 2,  Travis H Stracker 3,  Guillermo Montoya 6
Affiliations

Affiliations

  • 1 Structural Molecular Biology Group, Novo Nordisk Foundation Centre for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, Blegdamsvej 3B, 2200, Copenhagen, Denmark.
  • 2 Mass Spectrometry for Quantitative Proteomics, Novo Nordisk Foundation Centre for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, Blegdamsvej 3B, 2200, Copenhagen, Denmark.
  • 3 Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology (BIST), C/ Baldiri Reixac, 10, 08028, Barcelona, Spain.
  • 4 Protein Production and Characterization Platform, Novo Nordisk Foundation Centre for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, Blegdamsvej 3B, 2200, Copenhagen, Denmark.
  • 5 Macromolecular Crystallography Group, Structural Biology and Biocomputing Program, Spanish National Cancer Research Center (CNIO), c/Melchor Fernández Almagro 3, 28029, Madrid, Spain.
  • 6 Structural Molecular Biology Group, Novo Nordisk Foundation Centre for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, Blegdamsvej 3B, 2200, Copenhagen, Denmark. [email protected].
PMID: 29955062 DOI: 10.1038/s41467-018-04941-y
Abstract

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.

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