Wang Xinru, Bajaj Rakhi, Bollen Mathieu, Peti Wolfgang, Page Rebecca
Department of Molecular Biology, Cell Biology and Biochemistry, Brown University, Providence, RI 02912, USA.
Laboratory of Biosignaling & Therapeutics, Department of Cellular and Molecular Medicine, KU Leuven, 3000 Leuven, Belgium.
Structure. 2016 Dec 6;24(12):2174-2181. doi: 10.1016/j.str.2016.09.010. Epub 2016 Oct 27.
Specific interactions between proteins govern essential physiological processes including signaling. Many enzymes, especially the family of serine/threonine phosphatases (PSPs: PP1, PP2A, and PP2B/calcineurin/CN), recruit substrates and regulatory proteins by binding short linear motifs (SLiMs), short sequences found within intrinsically disordered regions that mediate specific protein-protein interactions. While tremendous progress had been made in identifying where and how SLiMs bind PSPs, especially PP1 and CN, essentially nothing is known about how SLiMs bind PP2A, a validated cancer drug target. Here we describe three structures of a PP2A-SLiM interaction (B56:pS-RepoMan, B56:pS-BubR1, and B56:pSpS-BubR1), show that this PP2A-specific SLiM is defined as LSPIxE, and then use these data to discover scores of likely PP2A regulators and substrates. Together, these data provide a powerful approach not only for dissecting PP2A interaction networks in cells but also for targeting PP2A diseases, such as cancer.
蛋白质之间的特异性相互作用支配着包括信号传导在内的重要生理过程。许多酶，尤其是丝氨酸/苏氨酸磷酸酶家族（PSPs：PP1、PP2A和PP2B/钙调神经磷酸酶/CN），通过结合短线性基序（SLiMs）来招募底物和调节蛋白，这些短序列存在于内在无序区域内，介导特异性蛋白质-蛋白质相互作用。虽然在确定SLiMs与PSPs（尤其是PP1和CN）的结合位置和方式方面已经取得了巨大进展，但对于SLiMs如何结合PP2A（一种经过验证的癌症药物靶点）基本上一无所知。在这里，我们描述了PP2A-SLiM相互作用的三种结构（B56:pS-RepoMan、B56:pS-BubR1和B56:pSpS-BubR1），表明这种PP2A特异性SLiM被定义为LSPIxE，然后利用这些数据发现了许多可能的PP2A调节因子和底物。总之，这些数据不仅为剖析细胞中的PP2A相互作用网络提供了一种强大的方法，也为针对PP2A相关疾病（如癌症）提供了方法。
