Trans-activation of the DNA-damage signalling protein kinase Chk2 by T-loop exchange
Trans-activation of the DNA-damage signalling protein kinase Chk2 by T-loop exchange
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DOI：
10.1038/sj.emboj.7601209
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发表时间：
2006-07-12
期刊：
影响因子：
11.4
通讯作者：
Pearl, Laurence H.
中科院分区：
文献类型：
--
作者：
Oliver, Antony W.;Paul, Angela;Pearl, Laurence H.
蛋白激酶Chk2(Checkpoint Kinase2)是复制检查点的主要效应因子。Chk2的激活是通过ATM对丝氨酸-谷氨酰胺/苏氨酸-谷氨酰胺簇区(SCD)中Thr68的磷酸化来启动的。磷酸化的SCD片段与第二个Chk2分子的FHA结构域结合，促进蛋白质的二聚化，并触发激活域中激活片段/T-环的磷酸化。我们现在已经确定了人Chk2与ADP和小分子抑制剂Debromohymenialdisine的络合物中的激活域的结构。该结构揭示了一种显著的二聚体排列，其中T-环在原体之间交换，以形成反式的活性激酶构象。生化数据表明，该二聚体是ATM-磷酸化促进的生物活性状态，也表明了反式磷酸化二聚化驱动Chk2激活的机制。
The protein kinase Chk2 (checkpoint kinase 2) is a major effector of the replication checkpoint. Chk2 activation is initiated by phosphorylation of Thr68, in the serine glutamine/threonine-glutamine cluster domain (SCD), by ATM. The phosphorylated SCD-segment binds to the FHA domain of a second Chk2 molecule, promoting dimerisation of the protein and triggering phosphorylation of the activation segment/T-loop in the kinase domain. We have now determined the structure of the kinase domain of human Chk2 in complexes with ADP and a small-molecule inhibitor debromohymenialdisine. The structure reveals a remarkable dimeric arrangement in which T-loops are exchanged between protomers, to form an active kinase conformation in trans. Biochemical data suggest that this dimer is the biologically active state promoted by ATM-phosphorylation, and also suggests a mechanism for dimerisation-driven activation of Chk2 by trans-phosphorylation.