Cai Zhenjian, Chehab Nabil H, Pavletich Nikola P
Structural Biology Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA.
Mol Cell. 2009 Sep 24;35(6):818-29. doi: 10.1016/j.molcel.2009.09.007.
The CHK2 protein kinase is an important transducer of DNA damage checkpoint signals, and its mutation contributes to hereditary and sporadic cancer. CHK2 activation is triggered by the phosphorylation of Thr68 by the DNA damage-activated ATM kinase. This leads to transient CHK2 dimerization, in part through intermolecular phosphoThr68-FHA domain interactions. Dimerization promotes kinase activation through activation-loop autophosphorylation, but the mechanism of this process has not been clear. The dimeric crystal structure of CHK2, described here, in conjunction with biochemical and mutational data reveals that productive CHK2 dimerization additionally involves intermolecular FHA-kinase domain and FHA-FHA interactions. Ile157, mutated in the Li-Fraumeni cancer-predisposition syndrome, plays a central role in the FHA-kinase domain interface, explaining the lack of dimerization and autophosphorylation of this mutant. In the dimer, the kinase active sites face each other in close proximity, indicating that dimerization may also serve to optimally position the kinase active sites for efficient activation loop transphosphorylation.
CHK2蛋白激酶是DNA损伤检查点信号的重要转导因子，其突变会导致遗传性和散发性癌症。CHK2的激活由DNA损伤激活的ATM激酶将苏氨酸68磷酸化所触发。这会导致CHK2短暂二聚化，部分是通过分子间磷酸化苏氨酸68-FHA结构域相互作用实现的。二聚化通过激活环自身磷酸化促进激酶激活，但这一过程的机制尚不清楚。本文描述的CHK2二聚体晶体结构，结合生化和突变数据表明，有效的CHK2二聚化还涉及分子间FHA-激酶结构域和FHA-FHA相互作用。在李-弗劳梅尼癌症易感综合征中发生突变的异亮氨酸157，在FHA-激酶结构域界面中起核心作用，解释了该突变体缺乏二聚化和自身磷酸化的原因。在二聚体中，激酶活性位点彼此紧密相对，表明二聚化也可能有助于将激酶活性位点最佳定位，以实现有效的激活环转磷酸化。
