8ewy

Structure of Janus Kinase (JAK) dimer complexed with cytokine receptor intracellular domain

spinqualitylabelsall models 8ewy, resolution 5.50Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 8ewy is a 4 chain structure with sequence from Mus musculus. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: Electron Microscopy, Resolution 5.5Å Ligands: ADN, ADP Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function JAK1_MOUSE Tyrosine kinase of the non-receptor type, involved in the IFN-alpha/beta/gamma signal pathway. Kinase partner for the interleukin (IL)-2 receptor as well as interleukin (IL)-10 receptor. Kinase partner for the type I interferon receptor IFNAR2. In response to interferon-binding to IFNAR1-IFNAR2 heterodimer, phosphorylates and activates its binding partner IFNAR2, creating docking sites for STAT proteins. Directly phosphorylates STAT proteins but also activates STAT signaling through the transactivation of other JAK kinases associated with signaling receptors.[UniProtKB:P23458] Publication Abstract from PubMed 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 IFNlambdaR1 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. Structural basis of Janus kinase trans-activation.,Caveney NA, Saxton RA, Waghray D, Glassman CR, Tsutsumi N, Hubbard SR, Garcia KC Cell Rep. 2023 Mar 28;42(3):112201. doi: 10.1016/j.celrep.2023.112201. Epub 2023 , Mar 2. PMID:36867534 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Janus kinase 3D structures

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