Structural Biology Program, Kimmel Center for Biology and Medicine at the Skirball Institute, New York University School of Medicine, New York, New York, USA.
Nat Struct Mol Biol. 2012 Aug;19(8):754-9. doi: 10.1038/nsmb.2348. Epub 2012 Jul 22.
The protein tyrosine kinase JAK2 mediates signaling through numerous cytokine receptors. JAK2 possesses a pseudokinase domain (JH2) and a tyrosine kinase domain (JH1). Through unknown mechanisms, JH2 regulates the catalytic activity of JH1, and hyperactivating mutations in the JH2 region of human JAK2 cause myeloproliferative neoplasms (MPNs). We showed previously that JAK2 JH2 is, in fact, catalytically active. Here we present crystal structures of human JAK2 JH2, including both wild type and the most prevalent MPN mutant, V617F. The structures reveal that JH2 adopts the fold of a prototypical protein kinase but binds Mg-ATP noncanonically. The structural and biochemical data indicate that the V617F mutation rigidifies α-helix C in the N lobe of JH2, facilitating trans-phosphorylation of JH1. The crystal structures of JH2 afford new opportunities for the design of novel JAK2 therapeutics targeting MPNs.
蛋白酪氨酸激酶 JAK2 通过众多细胞因子受体介导信号转导。JAK2 具有一个假激酶结构域（JH2）和一个酪氨酸激酶结构域（JH1）。通过未知的机制，JH2 调节 JH1 的催化活性，而人类 JAK2 的 JH2 区域的激活突变导致骨髓增殖性肿瘤（MPNs）。我们之前曾表明 JAK2 JH2 实际上具有催化活性。在这里，我们展示了人类 JAK2 JH2 的晶体结构，包括野生型和最常见的 MPN 突变体 V617F。这些结构揭示了 JH2 采用了典型蛋白激酶的折叠，但非典型地结合了 Mg-ATP。结构和生化数据表明，V617F 突变使 JH2 的 N lobe 中的 α 螺旋 C 变得僵硬，从而促进 JH1 的转磷酸化。JH2 的晶体结构为设计针对 MPN 的新型 JAK2 治疗药物提供了新的机会。
