SH2 domains are common protein interaction domains able to recognize short aminoacidic sequences presenting a phosphorylated tyrosine (pY). In spite of their fundamental importance for cell physiology there is a lack of information about the mechanism by which these domains recognize and bind their natural ligands. The N-terminal SH2 (N-SH2) domain of PI3K mediates the interaction with different scaffolding proteins and is known to recognize a specific pY-X-X-M consensus sequence. These interactions are at the cross roads of different molecular pathways and play a key role for cell development and division. By combining mutagenesis, chemical kinetics and NMR, here we provide a complete characterization of the interaction between N-SH2 and a peptide mimicking the scaffolding protein Gab2. Our results highlight that N-SH2 is characterized by a remarkable structural plasticity, with the binding reaction being mediated by a diffused structural region and not solely by the residues located in the binding pocket. Furthermore, the analysis of kinetic data allow us to pinpoint an allosteric network involving residues far from the binding pocket involved in specificity. Results are discussed on the light of previous works on the binding properties of SH2 domains.

中文翻译：

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结合诱导在SH2域中的结构可塑性。

SH2结构域是常见的蛋白质相互作用结构域，能够识别呈现磷酸化酪氨酸（pY）的短氨基酸序列。尽管它们对细胞生理学至关重要，但仍缺乏有关这些域识别并结合其天然配体的机制的信息。PI3K的N末端SH2（N-SH2）结构域介导与不同支架蛋白的相互作用，已知可识别特定的pY-XXM共有序列。这些相互作用处于不同分子途径的交叉路口，对细胞发育和分裂起着关键作用。通过结合诱变，化学动力学和NMR，在这里我们提供N-SH2和模拟支架蛋白Gab2的肽之间相互作用的完整表征。我们的结果强调，N-SH2的特征是具有显着的结构可塑性，结合反应是由扩散的结构区域介导的，而不仅是由位于结合袋中的残基介导的。此外，动力学数据的分析使我们能够查明一个变构网络，该网络涉及的残基距离与特异性相关的结合口袋较远。根据先前关于SH2结构域的结合特性的工作讨论了结果。