Growth factor receptor-bound protein 2 (GRB2) is a trivalent adaptor protein and a key element in signal transduction. It interacts via its flanking nSH3 and cSH3 domains with the proline-rich domain (PRD) of the RAS activator SOS1 and via its central SH2 domain with phosphorylated tyrosine residues of receptor tyrosine kinases (RTKs; e.g. HER2). The elucidation of structural organization and mechanistic insights into GRB2 interactions, however, remain challenging due to their inherent flexibility. This study represents an important advance in our mechanistic understanding of how GRB2 links RTKs to SOS1. Accordingly, it can be proposed that (1) HER2 pYP-bound SH2 potentiates GRB2 SH3 domain interactions with SOS1 (an allosteric mechanism); (2) the SH2 domain blocks cSH3, enabling nSH3 to bind SOS1 first before cSH3 follows (an avidity-based mechanism); and (3) the allosteric behavior of cSH3 to other domains appears to be unidirectional, although there is an allosteric effect between the SH2 and SH3 domains.

中文翻译：

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控制其与 SOS1 相互作用的 GRB2 的分子内变构受磷酸酪氨酸配体调节

生长因子受体结合蛋白 2 (GRB2) 是一种三价衔接蛋白，是信号转导的关键要素。它通过其侧翼的 nSH3 和 cSH3 域与 RAS 激活剂 SOS1 的富含脯氨酸域 (PRD) 相互作用，并通过其中央 SH2 域与受体酪氨酸激酶 (RTK；例如 HER2) 的磷酸化酪氨酸残基相互作用。然而，由于其固有的灵活性，对 GRB2 相互作用的结构组织和机械洞察的阐明仍然具有挑战性。这项研究代表了我们对 GRB2 如何将 RTK 与 SOS1 联系起来的机制理解方面的重要进展。因此，可以提出 (1) HER2 pYP 结合的 SH2 增强了 GRB2 SH3 结构域与 SOS1 的相互作用（一种变构机制）；(2) SH2结构域阻断cSH3，使 nSH3 在跟随 cSH3 之前首先结合 SOS1（一种基于亲和力的机制）；(3) cSH3 对其他结构域的变构行为似乎是单向的，尽管 SH2 和 SH3 结构域之间存在变构效应。