8EWY

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

Summary for 8EWY

• Entry DOI: 10.2210/pdb8ewy/pdb
• EMDB information: 28649
• Descriptor: Tyrosine-protein kinase, Interferon lambda receptor 1, ADENOSINE, ... (4 entities in total)
• Functional Keywords: jak, kinase, cytokine, signaling protein
• Biological source: Mus musculus (house mouse); More
• Total number of polymer chains: 4
• Total formula weight: 293233.32

Authors

Caveney, N.A.,Saxton, R.A.,Waghray, D.,Garcia, K.C. (deposition date: 2022-10-24, release date: 2023-03-08, Last modification date: 2024-12-25)

Primary citation

Caveney, N.A.,Saxton, R.A.,Waghray, D.,Glassman, C.R.,Tsutsumi, N.,Hubbard, S.R.,Garcia, K.C.
Structural basis of Janus kinase trans-activation.
Cell Rep, 42:112201-112201, 2023

PubMed Abstract: 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.

PubMed: 36867534
DOI: 10.1016/j.celrep.2023.112201

Experimental method

ELECTRON MICROSCOPY (5.5 Å)