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.
authors: Bioinformatics Group, RIKEN Genomic Sciences Center, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama, Kanagawa 230-0045, Japan.
authors: Atsushi
authors: A
authors: Suenaga
authors: Anatoly B
authors: AB
authors: Kiyatkin
authors: Mariko
authors: M
authors: Hatakeyama
authors: Noriyuki
authors: N
authors: Futatsugi
authors: Noriaki
authors: N
authors: Okimoto
authors: Yoshinori
authors: Y
authors: Hirano
authors: Tetsu
authors: T
authors: Narumi
authors: Atsushi
authors: A
authors: Kawai
authors: Ryutaro
authors: R
authors: Susukita
authors: Takahiro
authors: T
authors: Koishi
authors: Hideaki
authors: H
authors: Furusawa
authors: Kenji
authors: K
authors: Yasuoka
authors: Naoki
authors: N
authors: Takada
authors: Yousuke
authors: Y
authors: Ohno
authors: Makoto
authors: M
authors: Taiji
authors: Toshikazu
authors: T
authors: Ebisuzaki
authors: Jan B
authors: JB
authors: Hoek
authors: Akihiko
authors: A
authors: Konagaya
authors: Boris N
authors: BN
authors: Kholodenko
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D033942:Adaptor Proteins, Vesicular Transport / Q000737:chemistry* / Q000378:metabolism; D001665:Binding Sites; D066298:In Vitro Techniques; D008958:Models, Molecular; D010766:Phosphorylation; D011487:Protein Conformation; D055765:Shc Signaling Adaptor Proteins; D013816:Thermodynamics; D014443:Tyrosine / Q000737:chemistry; D018909:src Homology Domains
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D033942:Adaptor Proteins, Vesicular Transport; D055765:Shc Signaling Adaptor Proteins; D014443:Tyrosine