Structure and Activation Mechanism of the CHK2 DNA Damage Checkpoint Kinase
作者： Zhenjian Cai , Nabil H. Chehab , Nikola P. Pavletich
DOI: 10.1016/J.MOLCEL.2009.09.007
关键词: Autophosphorylation 、 Kinase 、 Biochemistry 、 DNA 、 Materials science 、 G2-M DNA damage checkpoint 、 Mutant 、 Mutation 、 Cell biology 、 Checkpoint Kinase 2 、 Phosphorylation
摘要: The CHK2 protein kinase is an important transducer of DNA damage checkpoint signals, and its mutation contributes to hereditary sporadic cancer. activation triggered by the phosphorylation Thr68 damage-activated ATM kinase. This leads transient dimerization, in part through intermolecular phosphoThr68-FHA domain interactions. Dimerization promotes activation-loop autophosphorylation, but mechanism this process has not been clear. dimeric crystal structure CHK2, described here, conjunction with biochemical mutational data reveals that productive dimerization additionally involves FHA-kinase FHA-FHA Ile157, mutated Li-Fraumeni cancer-predisposition syndrome, plays a central role interface, explaining lack autophosphorylation mutant. In dimer, active sites face each other close proximity, indicating may also serve optimally position for efficient loop transphosphorylation.
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