Institute of Biochemistry and Molecular Biology II, Medical Faculty of the Heinrich-Heine University, 40225 Düsseldorf, Germany.
Department of Physical Chemistry I, Ruhr University Bochum, Bochum, Germany.
Biochem J. 2021 Jul 30;478(14):2793-2809. doi: 10.1042/BCJ20210105.
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.
生长因子受体结合蛋白 2（GRB2）是一种三价衔接蛋白，也是信号转导中的关键元件。它通过其侧翼的 nSH3 和 cSH3 结构域与 RAS 激活物 SOS1 的富含脯氨酸结构域（PRD）相互作用，并通过其中心 SH2 结构域与受体酪氨酸激酶（RTKs；例如 HER2）的磷酸化酪氨酸残基相互作用。然而，由于其固有灵活性，GRB2 相互作用的结构组织和机制见解的阐明仍然具有挑战性。本研究代表了我们对 GRB2 将 RTKs 与 SOS1 连接起来的机制理解的重要进展。因此，可以提出以下观点：（1）HER2 pYP 结合的 SH2 增强了 GRB2 SH3 结构域与 SOS1 的相互作用（变构机制）；（2）SH2 结构域阻断 cSH3，从而使 nSH3 能够先与 SOS1 结合，然后 cSH3 结合（基于亲和力的机制）；（3）cSH3 与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。
