TY - JOUR
T1 - Molecular basis of Tousled-Like Kinase 2 activation
AU - Mortuza, Gulnahar B.
AU - Hermida, Dario
AU - Pedersen, Anna-Kathrine
AU - Segura-Bayona, Sandra
AU - López-Méndez, Blanca
AU - Redondo, Pilar
AU - Rüther, Patrick
AU - Pozdnyakova, Irina
AU - Garrote, Ana M
AU - Muñoz, Inés G
AU - Villamor-Payà, Marina
AU - Jauset, Cristina
AU - Olsen, Jesper V.
AU - Stracker, Travis H.
AU - Montoya, Guillermo
PY - 2018
Y1 - 2018
N2 - 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.
AB - 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.
U2 - 10.1038/s41467-018-04941-y
DO - 10.1038/s41467-018-04941-y
M3 - Journal article
C2 - 29955062
VL - 9
SP - 2535
JO - Nature Communications
JF - Nature Communications
SN - 2041-1723
IS - 1
M1 - 2535
ER -