1] D. E. Shaw Research, New York, New York, USA. [2].
1] Kimmel Center for Biology and Medicine of the Skirball Institute, Department of Biochemistry and Molecular Pharmacology, New York University School of Medicine, New York, New York, USA. [2].
Nat Struct Mol Biol. 2014 Jul;21(7):579-84. doi: 10.1038/nsmb.2849. Epub 2014 Jun 11.
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 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.
Janus 激酶-2（JAK2）介导各种细胞因子的信号转导，包括促红细胞生成素和生长激素。JAK2 具有串联的假激酶和酪氨酸激酶结构域。假激酶结构域中的突变与人类骨髓增生性肿瘤（MPN）有因果关系。JAK2 串联激酶结构域的结构尚不清楚，因此假激酶介导的自动抑制和致病激活的分子基础仍然不清楚。通过蛋白-蛋白对接的分子动力学模拟，我们产生了 JAK2 假激酶和激酶结构域之间自动抑制相互作用的结构模型。我们的模型有一个显著特征，即几乎所有的疾病突变都映射到结构域界面，该特征得到了突变实验的支持。模拟表明，激酶结构域被假激酶结构域稳定在非活性状态，为 V617F（主要的 JAK2 MPN 突变）的高活性提供了分子依据。
