Research Institute for Biomedical Sciences, Tokyo University of Science, Noda-shi, Chiba, Japan.
PLoS One. 2013 Sep 30;8(9):e74482. doi: 10.1371/journal.pone.0074482. eCollection 2013.
Src homology 2 (SH2) domains play a critical role in cellular signal transduction. They bind to peptides containing phosphotyrosine (pY) with various specificities that depend on the flanking amino-acid residues. The SH2 domain of growth-factor receptor-bound protein 2 (Grb2) specifically recognizes pY-X-N-X, whereas the SH2 domains in phosphatidylinositol 3-kinase (PI3K) recognize pY-X-X-M. Binding of the pY site in CD28 (pY-M-N-M) by PI3K and Grb2 through their SH2 domains is a key step that triggers the CD28 signal transduction for T cell activation and differentiation. In this study, we determined the crystal structure of the Grb2 SH2 domain in complex with a pY-containing peptide derived from CD28 at 1.35 Å resolution. The peptide was found to adopt a twisted U-type conformation, similar to, but distinct from type-I β-turn. In all previously reported crystal structures, the peptide bound to the Grb2 SH2 domains adopts a type-I β-turn conformation, except those with a proline residue at the pY+3 position. Molecular modeling also suggests that the same peptide bound to PI3K might adopt a very different conformation.
Src 同源结构域 2 (SH2) 在细胞信号转导中起着至关重要的作用。它们与含有磷酸酪氨酸 (pY) 的肽结合，特异性取决于侧翼氨基酸残基。生长因子受体结合蛋白 2 (Grb2) 的 SH2 结构域特异性识别 pY-X-N-X，而磷脂酰肌醇 3-激酶 (PI3K) 的 SH2 结构域识别 pY-X-X-M。PI3K 和 Grb2 通过其 SH2 结构域结合 CD28 中 pY 位点 (pY-M-N-M) 是触发 CD28 信号转导以激活和分化 T 细胞的关键步骤。在这项研究中，我们以 1.35 Å 的分辨率确定了 Grb2 SH2 结构域与源自 CD28 的含 pY 肽的复合物的晶体结构。该肽呈扭曲的 U 型构象，与 I 型 β 转角相似，但又有所不同。在所有以前报道的晶体结构中，除了 pY+3 位置有脯氨酸残基的那些结构外，与 Grb2 SH2 结构域结合的肽均采用 I 型 β 转角构象。分子建模还表明，与 PI3K 结合的相同肽可能采用非常不同的构象。
