期刊
NATURE STRUCTURAL & MOLECULAR BIOLOGY
卷 19, 期 8, 页码 754-759出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/nsmb.2348
关键词
-
资金
- US National Institute of Allergy and Infectious Diseases [R21 AI095808]
- Medical Research Council of Academy of Finland
- Sigrid Juselius Foundation
- Finnish Cancer Foundation
- Competitive Research Funding and Centre of Laboratory Medicine of the Tampere University Hospital
- Maire Lisko Foundation
- Tampere Tuberculosis Foundation
- US National Cancer Institute training grant [T32 CA009161]
- US Department of Energy, National Center for Research Resources [P41 RR012408]
- National Institute of General Medical Sciences [P41 GM103473]
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 alpha-helix C in the N lobe of JH2, facilitating trans-phosphorylation of JH2. The crystal structures of JH2 afford new opportunities for the design of novel JAK2 therapeutics targeting MPNs.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据