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Structural basis of Janus kinase trans-activation.

Nathanael A Caveney1, Robert A Saxton2, Deepa Waghray2

  • 1Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA 94305, USA.

Cell Reports
|March 3, 2023
PubMed
Summary

This study reveals the cryoelectron microscopy structure of Janus kinase 1 (JAK1) complexes in a trans-activation state. These findings offer mechanistic insights into JAK-STAT signaling and allosteric JAK inhibition.

Keywords:
CP: Molecular biologycryo-EMcytokinejanus kinasephosphorylation

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Area of Science:

  • Biochemistry
  • Molecular Biology
  • Structural Biology

Background:

  • Janus kinases (JAKs) are critical mediators of cytokine receptor signaling.
  • JAK activation involves receptor and JAK dimerization, leading to JAK trans-phosphorylation.
  • Previous structures showed JAK1-IFNλR1 complexes but not a trans-activation-compatible state.

Purpose of the Study:

  • To elucidate the structural basis of JAK trans-activation.
  • To investigate JAK complexes in a putative trans-activation state using cryo-EM.
  • To expand structural insights to other JAK complexes and allosteric inhibition mechanisms.

Main Methods:

  • Cryo-electron microscopy (cryo-EM) was employed to determine the structure of JAK1 complexes.
  • The study focused on a mouse JAK1 complex in a putative trans-activation state.
  • Structural analysis was extended to other relevant JAK complexes.

Main Results:

  • The cryo-EM structure of a mouse JAK1 complex in a putative trans-activation state was determined.
  • The structure provides mechanistic insights into the crucial trans-activation step of JAK signaling.
  • The study expands understanding to other JAK complexes and allosteric inhibition.

Conclusions:

  • The elucidated structures offer a mechanistic understanding of JAK trans-activation.
  • These findings contribute to understanding allosteric mechanisms of JAK inhibition.
  • The research provides a structural basis for further JAK inhibitor development.