生物
蛋白激酶结构域
Janus激酶2
贾纳斯激酶
细胞生物学
酪氨酸激酶
突变
激酶
突变
遗传学
信号转导
基因
突变体
作者
Yibing Shan,Kavitha Gnanasambandan,Daniela Ungureanu,Eric T. Kim,Henrik M. Hammarén,Kazuo Yamashita,Olli Silvennoinen,David E. Shaw,Stevan R. Hubbard
摘要
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.
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