Structural basis of Janus kinase trans-activation.
Structural basis of Janus kinase trans-activation.
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DOI：
10.1016/j.celrep.2023.112201
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发表时间：
2023-03-28
期刊：
影响因子：
8.8
通讯作者：
中科院分区：
文献类型：
--
作者：
Janus激酶(JAKs)介导细胞因子受体下游的信号转导。细胞因子依赖的二聚化通过细胞膜传递，以驱动JAK的二聚化、反式磷酸化和激活。激活JAK进而使受体胞内区(ICD)磷酸化，导致信号转导和转录激活因子(STAT)家族转录因子的募集、磷酸化和激活。最近研究了与干扰素λR1ICD结合的JAK1二聚体的结构排列。虽然这揭示了JAKs的二聚化依赖的激活以及致癌突变在这一过程中的作用，但酪氨酸激酶(TK)结构域之间的距离与TK结构域之间的反式磷酸化事件不相容。在这里，我们报道了小鼠JAK1复合体在假定的反式激活状态下的冷冻电子显微镜结构，并将这些见解扩展到其他生理相关的JAK复合体，为JAK信号的关键反式激活步骤和JAK抑制的变构机制提供了机制洞察。Janus激酶(JAKs)通过其激活区的二聚化和激活来介导细胞因子信号转导。卡文尼等人。使用冷冻-EM和AI引导的建模来揭示JAK的反式激活机制和JAK抑制的变构机制。这为进一步开发抑制剂和深入了解JAK信号的基本机制提供了基础。
Janus kinases (JAKs) mediate signal transduction downstream of cytokine receptors. Cytokine-dependent dimerization is conveyed across the cell membrane to drive JAK dimerization, trans-phosphorylation, and activation. Activated JAKs in turn phosphorylate receptor intracellular domains (ICDs), resulting in the recruitment, phosphorylation, and activation of signal transducer and activator of transcription (STAT)-family transcription factors. The structural arrangement of a JAK1 dimer complex with IFNλR1 ICD was recently elucidated while bound by stabilizing nanobodies. While this revealed insights into the dimerization-dependent activation of JAKs and the role of oncogenic mutations in this process, the tyrosine kinase (TK) domains were separated by a distance not compatible with the trans-phosphorylation events between the TK domains. Here, we report the cryoelectron microscopy structure of a mouse JAK1 complex in a putative trans-activation state and expand these insights to other physiologically relevant JAK complexes, providing mechanistic insight into the crucial trans-activation step of JAK signaling and allosteric mechanisms of JAK inhibition. Janus kinases (JAKs) mediate cytokine signaling through dimerization and activation of their kinase domains. Caveney et al. use cryo-EM and AI-guided modeling to reveal the trans-activation mechanism of JAKs and allosteric mechanisms of JAK inhibition. This provides the basis for further inhibitor development and insight into the fundamental mechanisms of JAK signaling.
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影响因子：
64.8
作者：
Jumper J;Evans R;Pritzel A;Green T;Figurnov M;Ronneberger O;Tunyasuvunakool K;Bates R;Žídek A;Potapenko A;Bridgland A;Meyer C;Kohl SAA;Ballard AJ;Cowie A;Romera-Paredes B;Nikolov S;Jain R;Adler J;Back T;Petersen S;Reiman D;Clancy E;Zielinski M;Steinegger M;Pacholska M;Berghammer T;Bodenstein S;Silver D;Vinyals O;Senior AW;Kavukcuoglu K;Kohli P;Hassabis D
通讯作者：
Hassabis D
DOI：
10.1042/bcj20160085
发表时间：
2016-06-01
期刊：
The Biochemical journal
影响因子：
--
作者：
Leroy E;Dusa A;Colau D;Motamedi A;Cahu X;Mouton C;Huang LJ;Shiau AK;Constantinescu SN
通讯作者：
Constantinescu SN
影响因子：
32.4
作者：
Chen E;Staudt LM;Green AR
通讯作者：
Green AR
影响因子：
14.8
作者：
Kavanagh ME;Horning BD;Khattri R;Roy N;Lu JP;Whitby LR;Ye E;Brannon JC;Parker A;Chick JM;Eissler CL;Wong AJ;Rodriguez JL;Rodiles S;Masuda K;Teijaro JR;Simon GM;Patricelli MP;Cravatt BF
通讯作者：
Cravatt BF
DOI：
10.1107/s0907444904019158
发表时间：
2004-12-01
影响因子：
2.2
作者：
Emsley, P;Cowtan, K
通讯作者：
Cowtan, K