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Structural basis for the specific recognition of RET by the Dok1 phosphotyrosine binding domain

Ning Shi1, Sheng Ye, Mark Bartlam

  • 1Laboratory of Structural Biology, Tsinghua University and National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Science, Beijing 100084, China.

The Journal of Biological Chemistry
|November 11, 2003
PubMed

Insights

Dok1 protein

Area of Science:

  • Molecular biology
  • Structural biology
  • Biochemistry

Background:

  • Dok1 is a substrate of activated protein-tyrosine kinases, involved in ras signaling and JNK activation.
  • Dok1 is constitutively phosphorylated in chronic myelogenous leukemia cells.
  • The phosphotyrosine binding (PTB) domain of Dok1 recognizes phosphotyrosine motifs on receptors.

Purpose of the Study:

  • To determine the crystal structure of the Dok1 PTB domain.
  • To elucidate the structural basis for Dok1's specific binding to phosphopeptides.
  • To investigate Dok1's recognition specificity compared to other PTB domains.

Main Methods:

  • X-ray crystallography was used to determine the structure of the Dok1 PTB domain.
  • Co-crystallization of the Dok1 PTB domain with a RET phosphopeptide was performed.
  • Structural analysis of the Dok1 PTB domain-RET phosphopeptide complex was conducted.

Main Results:

  • The crystal structure of the Dok1 PTB domain alone and complexed with a RET phosphopeptide was determined.
  • The Dok1 PTB domain adopts a beta-sandwich fold with an N-terminal alpha-helix.
  • The RET phosphopeptide binds to Dok1 within a surface groove, revealing the molecular basis for specific recognition.

Conclusions:

  • The study reveals the molecular mechanism underlying the specific recognition of RET by the Dok1 PTB domain.
  • Dok1 exhibits specificity, not recognizing peptides from TrkA or IL-4.
  • These findings provide insights into Dok1's role in signaling pathways and its potential as a therapeutic target.

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