Protein phosphorylation is a very common post-translational modification, catalyzed by kinases, for signaling and regulation. Phosphotyrosines frequently target SH2 domains. The spleen tyrosine kinase (Syk) is critical for tyrosine phosphorylation of multiple proteins and for regulation of important pathways. Phosphorylation of both Y342 and Y346 in Syk linker B is required for optimal signaling. The SH2 domains of Vav1 and PLC-γ both bind this doubly phosphorylated motif. Here we used a recently developed method to calculate the effects of Y342 and Y346 phosphorylation on the rate constants of a peptide from Syk linker B binding to the SH2 domains of Vav1 and PLC-γ. The predicted effects agree well with experimental observations. Moreover, we found that the same doubly phosphorylated peptide binds the two SH2 domains via distinct mechanism, with apparent rigid docking for Vav1 SH2 and dock-and-coalesce for PLC-γ SH2.

中文翻译：

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磷酸酪氨酰肽与两个 SH2 结构域结合的不同机制

蛋白质磷酸化是一种非常常见的翻译后修饰，由激酶催化，用于信号传导和调节。磷酸酪氨酸经常靶向 SH2 结构域。脾酪氨酸激酶 (Syk) 对于多种蛋白质的酪氨酸磷酸化和重要途径的调节至关重要。Syk 接头 B 中 Y342 和 Y346 的磷酸化是最佳信号传导所必需的。Vav1 和 PLC-γ 的 SH2 结构域都与这种双磷酸化基序结合。在这里，我们使用最近开发的方法来计算 Y342 和 Y346 磷酸化对来自 Syk 接头 B 的肽与 Vav1 和 PLC-γ 的 SH2 结构域结合的速率常数的影响。预测的效果与实验观察非常吻合。此外，我们发现相同的双磷酸化肽通过不同的机制结合两个 SH2 结构域，