期刊
SCIENCE
卷 376, 期 6589, 页码 163-+出版社
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/science.abn8933
关键词
-
资金
- National Institutes of Health [R37AI51321]
- Howard Hughes Medical Institute
- Ludwig Institute for Cancer Research
- Helen Hay Whitney Foundation
- National Science Foundation [DGE-1656518]
- Human Frontier Science Program Organization Fellowship [LT000011/2016-L]
Cytokines signal through cell surface receptor dimers to initiate activation of intracellular JAKs. This study reports the cryo-electron microscopy structure of JAK1 complexed with a cytokine receptor, and investigates the role of oncogenic JAK1 mutations in signaling.
Cytokines signal through cell surface receptor dimers to initiate activation of intracellular Janus kinases (JAKs). We report the 3.6-angstrom-resolution cryo-electron microscopy structure of full-length JAK1 complexed with a cytokine receptor intracellular domain Box1 and Box2 regions captured as an activated homodimer bearing the valine >phenylalanine (VF) mutation prevalent in myeloproliferative neoplasms. The seven domains of JAK1 form an extended structural unit, the dimerization of which is mediated by close-packing of the pseudokinase (PK) domains from the monomeric subunits. The oncogenic VF mutation lies within the core of the JAK1 PK interdimer interface, enhancing packing complementarity to facilitate ligand-independent activation. The carboxy-terminal tyrosine kinase domains are poised for transactivation and to phosphorylate the receptor STAT (signal transducer and activator of transcription)-recruiting motifs projecting from the overhanging FERM (four-point-one, ezrin, radixin, moesin)-SH2 (Src homology 2)-domains. Mapping of constitutively active JAK mutants supports a two-step allosteric activation mechanism and reveals opportunities for selective therapeutic targeting of oncogenic JAK signaling.
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