研究人员报告了全长的JAK1与细胞因子受体的细胞内Box1/Box2结构域复合的3.6Å分辨率冷冻电镜结构，该结构被捕获为带有在骨髓增生性肿瘤中普遍存在的Val→Phe（VF）突变的活化同源物。JAK1的七个结构域形成了一个扩展的结构单元，其二聚体化是由紧密包装的假激酶（PK）结构域介导的。致癌性的VF突变位于JAK1 PK二聚体界面的核心，增强了包装的互补性以促进配体独立的激活。
C-末端的酪氨酸激酶结构域准备对从悬垂的FERM-SH2结构域投射出来的受体STAT招募模体进行磷酸化。组成性活化的JAK突变体的映射支持两步异构激活机制，并揭示了选择性治疗致癌JAK信号的新机会。
据悉，细胞因子通过细胞表面受体二聚体发出信号，启动了细胞内JAK的激活。
附：英文原文
Title: Structure of a Janus kinase cytokine receptor complex reveals the basis for dimeric activation
Author: Caleb R. Glassman, Naotaka Tsutsumi, Robert A. Saxton, Patrick J. Lupardus, Kevin M. Jude, K. Christopher Garcia
Issue&Volume: 2022-03-10
Abstract: Cytokines signal through cell surface receptor dimers to initiate activation of intracellular Janus Kinases (JAKs). We report the 3.6- resolution cryo-EM structure of full-length JAK1 complexed with a cytokine receptor intracellular Box1/Box2 domain, captured as an activated homodimer bearing the Val→Phe (VF) mutation prevalent in myeloproliferative neoplasms. The seven domains of JAK1 form an extended structural unit whose dimerization is mediated by close-packed pseudokinase (PK) domains. The oncogenic VF mutation lies within the core of the JAK1 PK dimer interface, enhancing packing complementarity to facilitate ligand-independent activation. The C-terminal tyrosine kinase domains are poised to phosphorylate the receptor STAT-recruiting motifs projecting from the overhanging FERM-SH2 domains. Mapping of constitutively active JAK mutants supports a two-step allosteric activation mechanism and reveals new opportunities for selective therapeutic targeting of oncogenic JAK signaling.
DOI: abn8933
Source: https://www.science.org/doi/10.1126/science.abn8933