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-Structure paper
タイトル | Structural basis of Janus kinase trans-activation. |
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ジャーナル・号・ページ | Cell Rep, Vol. 42, Issue 3, Page 112201, Year 2023 |
掲載日 | 2023年3月1日 |
著者 | Nathanael A Caveney / Robert A Saxton / Deepa Waghray / Caleb R Glassman / Naotaka Tsutsumi / Stevan R Hubbard / K Christopher Garcia / |
PubMed 要旨 | Janus kinases (JAKs) mediate signal transduction downstream of cytokine receptors. Cytokine-dependent dimerization is conveyed across the cell membrane to drive JAK dimerization, trans- ...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. |
リンク | Cell Rep / PubMed:36867534 / PubMed Central |
手法 | EM (単粒子) |
解像度 | 5.5 Å |
構造データ | EMDB-28649, PDB-8ewy: |
化合物 | ChemComp-ADN: ChemComp-ADP: |
由来 |
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キーワード | SIGNALING PROTEIN / JAK / Kinase / Cytokine |