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Structure paper

TitleStructural basis of Janus kinase trans-activation.
Journal, issue, pagesCell Rep, Vol. 42, Issue 3, Page 112201, Year 2023
Publish dateMar 28, 2023
AuthorsNathanael A Caveney / Robert A Saxton / Deepa Waghray / Caleb R Glassman / Naotaka Tsutsumi / Stevan R Hubbard / K Christopher Garcia /
PubMed AbstractJanus 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.
External linksCell Rep / PubMed:36867534 / PubMed Central
MethodsEM (single particle)
Resolution5.5 Å
Structure data

28649

8ewy

EMDB-28649, PDB-8ewy:
Structure of Janus Kinase (JAK) dimer complexed with cytokine receptor intracellular domain
Method: EM (single particle) / Resolution: 5.5 Å

Chemicals

ChemComp-ADN:
ADENOSINE

ChemComp-ADP:
ADENOSINE-5'-DIPHOSPHATE / ADP, energy-carrying molecule*YM

Source
  • mus musculus (house mouse)
KeywordsSIGNALING PROTEIN / JAK / Kinase / Cytokine

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