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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^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.