A Conserved Allosteric Pathway in Tyrosine Kinase Regulation

William M. Marsiglia, Joseph Katigbak, Sijin Zheng, Moosa Mohammadi, Yingkai Zhang, Nathaniel J. Traaseth

Research output: Contribution to journalArticlepeer-review


An autoinhibitory network of hydrogen bonds located at the kinase hinge (referred to as the "molecular brake") regulates the activity of several receptor tyrosine kinases. The mechanism whereby mutational disengagement of the brake allosterically activates the kinase in human disease is incompletely understood. We used a combination of NMR, bioinformatics, and molecular dynamics simulation to show that mutational disruption of the molecular brake triggers localized conformational perturbations that propagate to the active site. This entails changes in interactions of an isoleucine, one of three hydrophobic residues that lock the phenylalanine of the DFG motif in an inactive conformation. Structural analysis of tyrosine kinases provides evidence that this allosteric control mechanism is shared across the tyrosine kinase family. We also show that highly activating mutations at the brake diminish the enzyme's thermostability, thereby explaining why these mutations cause milder skeletal syndromes compared with less-activating mutations in the activation loop.

Original languageEnglish (US)
Pages (from-to)1308-1315.e3
Issue number8
StatePublished - Aug 6 2019


  • FGF receptor
  • NMR spectroscopy
  • allostery
  • pathogenic mutations
  • tyrosine kinases
  • Catalytic Domain
  • Magnetic Resonance Spectroscopy
  • Allosteric Regulation
  • Humans
  • Isoleucine/genetics
  • Protein-Tyrosine Kinases/chemistry
  • Molecular Dynamics Simulation
  • Hydrophobic and Hydrophilic Interactions
  • Protein Conformation
  • Mutation

ASJC Scopus subject areas

  • Molecular Biology
  • Structural Biology


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