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Structural insights into FRS2α PTB domain recognition by neurotrophin receptor TrkB

Lei Zeng1, Miklos Kuti, Shiraz Mujtaba

  • 1Department of Structural and Chemical Biology, Icahn School of Medicine at Mount Sinai, New York, New York, 10029.

Proteins
|January 29, 2014
PubMed

Insights

Fibroblast growth factor receptor (FGFR) substrate 2 alpha (FRS2α) scaffolding proteins bind receptor tyrosine kinases. Structural analysis reveals distinct pockets in the FRS2α PTB domain, enabling targeted drug design.

Area of Science:

  • Molecular biology
  • Structural biology
  • Biochemistry

Background:

  • Fibroblast growth factor receptor (FGFR) substrate 2 (FRS2) proteins act as crucial scaffolding adapters for receptor tyrosine kinases (RTKs).
  • FRS2α proteins mediate signal transduction from activated RTKs to downstream effectors via their phosphotyrosine-binding (PTB) domain.

Purpose of the Study:

  • To determine the nuclear magnetic resonance (NMR) structure of the FRS2α PTB domain in complex with phosphorylated TrkB.
  • To elucidate the structural basis for FRS2α-PTB domain interactions with RTKs and phosphorylated peptides.

Main Methods:

  • Nuclear magnetic resonance (NMR) spectroscopy was employed to determine the 3D structure.
  • Structural analysis focused on the FRS2α PTB domain and its binding interfaces.

Main Results:

  • The NMR structure revealed the FRS2α PTB domain possesses two adjacent, distinct pockets.
  • These pockets facilitate mutually exclusive binding to either the nonphosphorylated juxtamembrane region of FGFR or tyrosine-phosphorylated peptides like TrkA and TrkB.
  • This structural plasticity highlights the FRS2α PTB domain's adaptable binding capabilities.

Conclusions:

  • The determined structure provides novel insights into the FRS2α PTB domain's interaction mechanisms.
  • These findings suggest a rational approach for designing selective small molecule inhibitors by targeting the identified pockets.
  • This could lead to the development of therapeutics modulating RTK signaling pathways.
Keywords:
FGFRFRS2NMRPTBRTKSNTTrkneurotrophin receptorsolution structure

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