Molecular basis for pseudokinase-dependent autoinhibition of JAK2 tyrosine kinase.
Molecular basis for pseudokinase-dependent autoinhibition of JAK2 tyrosine kinase.
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DOI：
10.1038/nsmb.2849
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发表时间：
2014-07
影响因子：
16.8
通讯作者：
Hubbard SR
中科院分区：
文献类型：
--
作者：
Shan Y;Gnanasambandan K;Ungureanu D;Kim ET;Hammarén H;Yamashita K;Silvennoinen O;Shaw DE;Hubbard SR
Janus kinase2(JAK2)通过促红细胞生成素和生长激素等多种细胞因子介导信号传导。JAK2具有串联的假激酶和酪氨酸激酶结构域。假激酶域的突变与人类的骨髓增生性肿瘤(MPN)有因果关系。JAK2串联激动域的结构尚不清楚，因此，伪激酶介导的自身抑制和致病激活的分子基础仍然不清楚。利用蛋白质-蛋白质对接的无偏分子动力学模拟，我们建立了JAK2假激酶和激活域之间的自抑制相互作用的结构模型。我们模型的一个显著特点是几乎所有的疾病突变都映射到结构域界面，这一点得到了突变实验的支持。模拟结果表明，假激活区将激活域稳定在非活性状态，并为JAK2 MPN的主要突变V617F的高活性提供了分子基础。
Janus kinase-2 (JAK2) mediates signaling by various cytokines, including erythropoietin and growth hormone. JAK2 possesses tandem pseudokinase and tyrosine kinase domains. Mutations in the pseudokinase domain are causally linked to myeloproliferative neoplasms (MPNs) in humans. The structure of the JAK2 tandem kinase domains is unknown, and therefore the molecular bases for pseudokinase-mediated autoinhibition and pathogenic activation remain obscure. Using unbiased molecular dynamics simulations of protein-protein docking, we produced a structural model for the autoinhibitory interaction between the JAK2 pseudokinase and kinase domains. A striking feature of our model, which is supported by mutagenesis experiments, is that nearly all of the disease mutations map to the domain interface. The simulations indicate that the kinase domain is stabilized in an inactive state by the pseudokinase domain, and they offer a molecular rationale for the hyperactivity of V617F, the predominant JAK2 MPN mutation.