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Molecular dynamics simulations reveal that Tyr-317 phosphorylation reduces Shc binding affinity for phosphotyrosyl

Atsushi Suenaga1, Mariko Hatakeyama, Anatoly B Kiyatkin

  • 1Computational and Experimental System Biology Group, RIKEN Genomic Sciences Center, Yokohama, Kanagawa 230-0046, Japan.

Biophysical Journal
|March 18, 2009
PubMed

Insights

Tyrosine phosphorylation of Shc protein alters its structure, affecting its binding to epidermal growth factor receptor (EGFR). This phosphorylation regulates how Shc interacts with signaling partners, impacting cell communication.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Cell Signaling

Background:

  • The Src homology 2 (SH2) and collagen domain protein Shc is crucial for signal transduction pathways involving tyrosine kinase receptors like EGFR.
  • Shc's SH2 and phospho-tyrosine binding (PTB) domains mediate interactions with activated receptors.
  • Phosphorylation of Shc at Tyr-317 initiates downstream signaling cascades, including Ras-MAPK pathway activation.

Purpose of the Study:

  • To investigate the conformational changes in full-length Shc protein induced by Tyr-317 phosphorylation.
  • To understand how Tyr-317 phosphorylation affects Shc interactions with the epidermal growth factor receptor (EGFR).

Main Methods:

  • Molecular dynamics simulations of full-length Shc protein.
  • Computational estimation of binding affinities between Shc and EGFR-derived peptides.

Main Results:

  • Shc tyrosine phosphorylation causes significant domain rearrangement, indicating a major conformational change.
  • Binding affinity studies revealed that unphosphorylated Shc binds EGFR-derived phosphotyrosyl peptides more strongly than phosphorylated Shc.
  • A novel phenomenon is identified where linker region phosphorylation modulates SH2 and PTB domain binding affinity.

Conclusions:

  • Tyrosine phosphorylation of Shc at Tyr-317 is a key regulatory mechanism controlling its interaction with signaling partners.
  • This phosphorylation-dependent modulation of binding affinity has significant implications for the dynamics of cellular signaling pathways.
  • The findings provide novel structural insights into Shc protein function in EGFR signaling.

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