ACS Chem Biol. 2012 Apr 20;7(4):678-82. doi: 10.1021/cb200487h. Epub 2012 Feb 3.
p27(Kip1) (p27), a prototypical intrinsically disordered protein (IDP), regulates eukaryotic cell division through interactions with cyclin-dependent kinase (Cdk)/cyclin complexes. The activity, stability, and subcellular localization of p27 are regulated by phosphorylation. We illustrate how p27 integrates regulatory signals from several non-receptor tyrosine kinases (NRTKs) to activate Cdk4 and initiate cell cycle entry. Unmodified p27 potently inhibits Cdk/cyclin complexes, including Cdk4/cyclin D (IC(50), 1 nM). Some NRTKs (e.g., Abl) phosphorylate p27 on Tyr 88, which facilitates a second modification on Tyr 74 by another NRTK (e.g., Src). Importantly, this second modification causes partial reactivation of Cdk4 within ternary complexes containing doubly Tyr phosphorylated p27. Partial activation of Cdk4 initiates entry into the cell division cycle. Therefore, p27's disordered features enable NRTKs to sequentially promote a phosphorylation cascade that controls cell fate. Beyond cell cycle control, these results illustrate general concepts regarding why IDPs are well-suited for roles in signaling and regulation in biological systems.
p27（Kip1）（p27）是一种典型的无序蛋白（IDP），通过与细胞周期蛋白依赖性激酶（Cdk）/细胞周期蛋白复合物相互作用来调节真核细胞分裂。p27 的活性、稳定性和亚细胞定位受磷酸化调节。我们展示了 p27 如何整合来自几种非受体酪氨酸激酶（NRTK）的调节信号，以激活 Cdk4 并启动细胞周期进入。未修饰的 p27 强烈抑制 Cdk/细胞周期蛋白复合物，包括 Cdk4/细胞周期蛋白 D（IC50，1 nM）。一些 NRTK（例如 Abl）在 Tyr88 上磷酸化 p27，这有利于另一个 NRTK（例如 Src）在 Tyr74 上进行第二次修饰。重要的是，第二次修饰导致包含双 Tyr 磷酸化 p27 的三元复合物中的 Cdk4 部分重新激活。Cdk4 的部分激活启动细胞分裂周期的进入。因此，p27 的无序特征使 NRTK 能够顺序促进控制细胞命运的磷酸化级联反应。除了细胞周期控制之外，这些结果还说明了为什么 IDP 非常适合在生物系统中的信号转导和调节中发挥作用的一般概念。
