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Molecular Dynamics Simulation Analysis of JAK1 Initial Activation: Phosphorylation-Induced Conformational Dynamics

Xinyu Peng1, Kefu Liu1, Guodong Chen2

  • 1Department of Biomedical Informatic, School of Life Sciences, Central South University, Changsha 410083, China.

Life (Basel, Switzerland)
|August 28, 2025
PubMed

Insights

Phosphorylation of Janus kinase 1 (JAK1) at tyrosine residues Y1034 and Y1035 promotes its opening. Bisphosphorylation, especially at Y1035, is key for JAK1 activation, offering disease intervention insights.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Structural Biology

Background:

  • Janus kinase (JAK) is crucial for cytokine signaling.
  • JAK hyperactivation drives various diseases.
  • The precise activation mechanism of JAK1 remains elusive.

Purpose of the Study:

  • To investigate the role of tyrosine residues Y1034 and Y1035 in JAK1 activation.
  • To elucidate the molecular mechanisms of JAK1 conformational changes.
  • To provide insights for therapeutic targeting of JAK1.

Main Methods:

  • Utilized molecular dynamics (MD) simulations.
  • Analyzed conformational transitions of the JAK1 tyrosine kinase (TK) domain.
  • Investigated the impact of phosphorylation at Y1034 and Y1035.

Main Results:

  • Bisphosphorylation at Y1034 and Y1035 promotes the transition to JAK1's open conformation.
  • pY1035 has a more significant role than pY1034 in promoting opening.
  • Phosphorylation increases negative surface charge, aiding TK-FERM domain dissociation.
  • Stable hydrogen bonds in a loop region partially hinder full activation.

Conclusions:

  • Phosphorylation of Y1034 and Y1035 is critical for initial JAK1 activation.
  • pY1035 plays a dominant role in the conformational shift to the open state.
  • Understanding these mechanisms can inform strategies for treating JAK1-related diseases.
Keywords:
DelphiJAKJAK activationelectrostaticmolecular dynamic simulationstyrosine phosphorylation

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