Tyr-317 Phosphorylation Increases Shc Structural Rigidity and Reduces Coupling of Domain Motions Remote from the Phosphorylation Site as Revealed by Molecular Dynamics Simulations

Atsushi Suenaga, Anatoly B. Kiyatkin, Mariko Hatakeyama, Noriyuki Futatsugi, Noriaki Okimoto, Yoshinori Hirano, Tetsu Narumi, Atsushi Kawai, Ryutaro Susukita, Takahiro Koishi, Hideaki Furusawa, Kenji Yasuoka, Naoki Takada, Yousuke Ohno, Makoto Taiji, Toshikazu Ebisuzaki, Jan B. Hoek, Akihiko Konagaya, Boris N. Kholodenko

研究成果: Article査読

27 被引用数 (Scopus)

抄録

Activated receptor tyrosine kinases bind the Shc adaptor protein through its N-terminal phosphotyrosine-binding (PTB) and C-terminal Src homology 2 (SH2) domains. After binding, Shc is phosphorylated within the central collagen-homology (CH) linker region on Tyr-317, a residue remote to both the PTB and SH2 domains. Shc phosphorylation plays a pivotal role in the initiation of mitogenic signaling through the Ras/Raf/MEK/ERK pathway, but it is unclear if Tyr-317 phosphorylation affects Shc-receptor interactions through the PTB and SH2 domains. To investigate the structural impact of Shc phosphorylation, molecular dynamics simulations were carried out using special-purpose Molecular Dynamics Machine-Grape computers. After a 1-nanosecond equilibration, atomic motions in the structures of unphosphorylated Shc and Shc phosphorylated on Tyr-317 were calculated during a 2-nanosecond period. The results reveal larger phosphotyrosine-binding domain fluctuations and more structural flexibility of unphosphorylated Shc compared with phosphorylated Shc. Collective motions between the PTB-SH2, PTB-CH, and CH-SH2 domains were highly correlated only in unphosphorylated Shc. Dramatic changes in domain coupling and structural rigidity, induced by Tyr-317 phosphorylation, may alter Shc function, bringing about marked differences in the association of unphosphorylated and phosphorylated Shc with its numerous partners, including activated membrane receptors.

本文言語English
ページ(範囲)4657-4662
ページ数6
ジャーナルJournal of Biological Chemistry
279
6
DOI
出版ステータスPublished - 2004 2 6

ASJC Scopus subject areas

  • 生化学
  • 分子生物学
  • 細胞生物学

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