Structural basis of Janus kinase trans-activation

• DOI: 10.1016/j.celrep.2023.112201
• Publication Date: 2023-03-02T05:40:44Z
• Authors: Nathanael A. Caveney; Robert A. Saxton; Deepa Waghray; Caleb R. Glassman; Naotaka Tsutsumi; Stevan R. Hubbard; K. Christopher Ga...
• Keywords: phosphorylation; QH301-705.5; Cryoelectron Microscopy; Janus Kinase 3; janus kinase; Janus Kinase 1; Janus Kinase 2; Article; DNA-Binding Proteins; Mice; cytokine; Trans-Activators; cryo-EM; Animals; Biology (General); Phosphorylation; Janus Kinases; Signal Transduction

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 recruitment, phosphorylation, activation transducer activator transcription (STAT)-family factors. The structural arrangement a JAK1 dimer complex with IFNλR1 ICD was recently elucidated while bound by stabilizing nanobodies. While this revealed insights into dimerization-dependent role oncogenic mutations process, tyrosine kinase (TK) were separated distance not compatible trans-phosphorylation events between TK domains. Here, we report cryoelectron microscopy structure mouse putative trans-activation state expand these other physiologically relevant complexes, providing mechanistic insight crucial step signaling allosteric mechanisms inhibition.