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

Research output: Contribution to journalArticle

27 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)4657-4662
Number of pages6
JournalJournal of Biological Chemistry
Volume279
Issue number6
DOIs
Publication statusPublished - 2004 Feb 6

Fingerprint

Phosphotyrosine
Phosphorylation
Molecular Dynamics Simulation
Rigidity
Molecular dynamics
src Homology Domains
Computer simulation
Collagen
Shc Signaling Adaptor Proteins
MAP Kinase Signaling System
Mitogen-Activated Protein Kinase Kinases
Vitis
Receptor Protein-Tyrosine Kinases
Association reactions
Membranes

ASJC Scopus subject areas

  • Biochemistry

Cite this

Tyr-317 Phosphorylation Increases Shc Structural Rigidity and Reduces Coupling of Domain Motions Remote from the Phosphorylation Site as Revealed by Molecular Dynamics Simulations. / Suenaga, Atsushi; Kiyatkin, Anatoly B.; Hatakeyama, Mariko; Futatsugi, Noriyuki; Okimoto, Noriaki; Hirano, Yoshinori; Narumi, Tetsu; Kawai, Atsushi; Susukita, Ryutaro; Koishi, Takahiro; Furusawa, Hideaki; Yasuoka, Kenji; Takada, Naoki; Ohno, Yousuke; Taiji, Makoto; Ebisuzaki, Toshikazu; Hoek, Jan B.; Konagaya, Akihiko; Kholodenko, Boris N.

In: Journal of Biological Chemistry, Vol. 279, No. 6, 06.02.2004, p. 4657-4662.

Research output: Contribution to journalArticle

Suenaga, A, Kiyatkin, AB, Hatakeyama, M, Futatsugi, N, Okimoto, N, Hirano, Y, Narumi, T, Kawai, A, Susukita, R, Koishi, T, Furusawa, H, Yasuoka, K, Takada, N, Ohno, Y, Taiji, M, Ebisuzaki, T, Hoek, JB, Konagaya, A & Kholodenko, BN 2004, 'Tyr-317 Phosphorylation Increases Shc Structural Rigidity and Reduces Coupling of Domain Motions Remote from the Phosphorylation Site as Revealed by Molecular Dynamics Simulations', Journal of Biological Chemistry, vol. 279, no. 6, pp. 4657-4662. https://doi.org/10.1074/jbc.M310598200
Suenaga, Atsushi ; Kiyatkin, Anatoly B. ; Hatakeyama, Mariko ; Futatsugi, Noriyuki ; Okimoto, Noriaki ; Hirano, Yoshinori ; Narumi, Tetsu ; Kawai, Atsushi ; Susukita, Ryutaro ; Koishi, Takahiro ; Furusawa, Hideaki ; Yasuoka, Kenji ; Takada, Naoki ; Ohno, Yousuke ; Taiji, Makoto ; Ebisuzaki, Toshikazu ; Hoek, Jan B. ; Konagaya, Akihiko ; Kholodenko, Boris N. / Tyr-317 Phosphorylation Increases Shc Structural Rigidity and Reduces Coupling of Domain Motions Remote from the Phosphorylation Site as Revealed by Molecular Dynamics Simulations. In: Journal of Biological Chemistry. 2004 ; Vol. 279, No. 6. pp. 4657-4662.
@article{380616ebd5494b2384578a66d54c1e9e,
title = "Tyr-317 Phosphorylation Increases Shc Structural Rigidity and Reduces Coupling of Domain Motions Remote from the Phosphorylation Site as Revealed by Molecular Dynamics Simulations",
abstract = "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.",
author = "Atsushi Suenaga and Kiyatkin, {Anatoly B.} and Mariko Hatakeyama and Noriyuki Futatsugi and Noriaki Okimoto and Yoshinori Hirano and Tetsu Narumi and Atsushi Kawai and Ryutaro Susukita and Takahiro Koishi and Hideaki Furusawa and Kenji Yasuoka and Naoki Takada and Yousuke Ohno and Makoto Taiji and Toshikazu Ebisuzaki and Hoek, {Jan B.} and Akihiko Konagaya and Kholodenko, {Boris N.}",
year = "2004",
month = "2",
day = "6",
doi = "10.1074/jbc.M310598200",
language = "English",
volume = "279",
pages = "4657--4662",
journal = "Journal of Biological Chemistry",
issn = "0021-9258",
publisher = "American Society for Biochemistry and Molecular Biology Inc.",
number = "6",

}

TY - JOUR

T1 - Tyr-317 Phosphorylation Increases Shc Structural Rigidity and Reduces Coupling of Domain Motions Remote from the Phosphorylation Site as Revealed by Molecular Dynamics Simulations

AU - Suenaga, Atsushi

AU - Kiyatkin, Anatoly B.

AU - Hatakeyama, Mariko

AU - Futatsugi, Noriyuki

AU - Okimoto, Noriaki

AU - Hirano, Yoshinori

AU - Narumi, Tetsu

AU - Kawai, Atsushi

AU - Susukita, Ryutaro

AU - Koishi, Takahiro

AU - Furusawa, Hideaki

AU - Yasuoka, Kenji

AU - Takada, Naoki

AU - Ohno, Yousuke

AU - Taiji, Makoto

AU - Ebisuzaki, Toshikazu

AU - Hoek, Jan B.

AU - Konagaya, Akihiko

AU - Kholodenko, Boris N.

PY - 2004/2/6

Y1 - 2004/2/6

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=10744228882&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=10744228882&partnerID=8YFLogxK

U2 - 10.1074/jbc.M310598200

DO - 10.1074/jbc.M310598200

M3 - Article

VL - 279

SP - 4657

EP - 4662

JO - Journal of Biological Chemistry

JF - Journal of Biological Chemistry

SN - 0021-9258

IS - 6

ER -