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A crystallographic snapshot of tyrosine trans-phosphorylation in action

Huaibin Chen1, Chong-Feng Xu, Jinghong Ma

  • 1Department of Pharmacology and Kimmel Center for Biology and Medicine at Skirball Institute, New York University School of Medicine, New York, NY 10016, USA.

Proceedings of the National Academy of Sciences of the United States of America
|December 9, 2008
PubMed

Insights

Researchers reveal the crystal structure of FGF receptor 2 kinases during Y769 trans-phosphorylation. This structural insight explains the high specificity and precision in receptor tyrosine kinase signaling.

Area of Science:

  • Biochemistry
  • Structural Biology
  • Molecular Signaling

Background:

  • Tyrosine trans-phosphorylation is crucial for receptor tyrosine kinase (RTK) signaling.
  • The precise structural mechanisms governing this process, particularly for FGFRs, remain largely undefined.

Purpose of the Study:

  • To elucidate the structural basis of tyrosine trans-phosphorylation in receptor tyrosine kinases.
  • To present the crystal structure of FGF receptor 2 (FGFR2) kinases during the trans-phosphorylation of Y769.

Main Methods:

  • X-ray crystallography to determine the structure of FGFR2 kinases.
  • Time-resolved mass spectrometry to analyze the trans-phosphorylation mechanism.

Main Results:

  • The crystal structure reveals specific, extensive interactions between enzyme- and substrate-acting kinases.
  • These interactions occur both near the active site and at distant regions, ensuring precise Y769 phosphorylation.
  • Time-resolved mass spectrometry supports the proposed trans-phosphorylation mechanism.

Conclusions:

  • The study provides a molecular framework for understanding FGFR2 trans-phosphorylation and its specificity.
  • The findings offer insights into Kallmann syndrome mutations and phosphorylation order in FGFRs.
  • The identified mechanism is likely applicable to other receptor tyrosine kinases.

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