Hao Bing, Zheng Ning, Schulman Brenda A, Wu Geng, Miller Julie J, Pagano Michele, Pavletich Nikola P
Howard Hughes Medical Institute, New York, New York 10021, USA.
Mol Cell. 2005 Oct 7;20(1):9-19. doi: 10.1016/j.molcel.2005.09.003.
The ubiquitin-mediated proteolysis of the Cdk2 inhibitor p27(Kip1) plays a central role in cell cycle progression, and enhanced degradation of p27(Kip1) is associated with many common cancers. Proteolysis of p27(Kip1) is triggered by Thr187 phosphorylation, which leads to the binding of the SCF(Skp2) (Skp1-Cul1-Rbx1-Skp2) ubiquitin ligase complex. Unlike other known SCF substrates, p27(Kip1) ubiquitination also requires the accessory protein Cks1. The crystal structure of the Skp1-Skp2-Cks1 complex bound to a p27(Kip1) phosphopeptide shows that Cks1 binds to the leucine-rich repeat (LRR) domain and C-terminal tail of Skp2, whereas p27(Kip1) binds to both Cks1 and Skp2. The phosphorylated Thr187 side chain of p27(Kip1) is recognized by a Cks1 phosphate binding site, whereas the side chain of an invariant Glu185 inserts into the interface between Skp2 and Cks1, interacting with both. The structure and biochemical data support the proposed model that Cdk2-cyclin A contributes to the recruitment of p27(Kip1) to the SCF(Skp2)-Cks1 complex.
泛素介导的细胞周期蛋白依赖性激酶2（Cdk2）抑制剂p27（Kip1）的蛋白水解在细胞周期进程中起核心作用，p27（Kip1）降解增强与许多常见癌症相关。p27（Kip1）的蛋白水解由苏氨酸187磷酸化触发，这导致SCF（Skp2）（Skp1-Cul1-Rbx1-Skp2）泛素连接酶复合物的结合。与其他已知的SCF底物不同，p27（Kip1）的泛素化还需要辅助蛋白Cks1。与p27（Kip1）磷酸肽结合的Skp1-Skp2-Cks1复合物的晶体结构表明，Cks1与Skp2的富含亮氨酸重复序列（LRR）结构域和C末端尾巴结合，而p27（Kip1）与Cks1和Skp2都结合。p27（Kip1）磷酸化的苏氨酸187侧链被Cks1磷酸结合位点识别，而不变的谷氨酸185侧链插入Skp2和Cks1之间的界面，与两者相互作用。该结构和生化数据支持所提出的模型，即Cdk2-细胞周期蛋白A有助于将p27（Kip1）募集到SCF（Skp2）-Cks1复合物中。
