CKS1-DEPENDENT RECOGNITION OF P27(KIP1) BY THE SCF(SKP2) UBIQUITIN LIGASE

本子项目是利用由NIH/NCRR资助的中心赠款提供的资源的众多研究子项目之一。子项目和研究者（PI）可能已经从另一个NIH来源获得了主要资金，因此可以在其他CRISP条目中表示。列出的机构是中心的，不一定是研究者的机构。泛素介导的Cdk2抑制剂p27（Kip1）的蛋白水解在细胞周期进程中起着核心作用，p27（Kip1）的增强降解与许多常见癌症有关。Thr187磷酸化触发p27（Kip1）的蛋白水解，导致SCF(Skp2) （Skp1-Cul1-Rbx1-Skp2）泛素连接酶复合物结合。与其他已知的SCF底物不同，p27（Kip1）泛素化也需要辅助蛋白Cks1。结合p27（Kip1）磷酸肽的Skp1-Skp2-Cks1复合物的晶体结构表明，Cks1与Skp2的富含亮氨酸的重复序列（LRR）结构域和c末端尾部结合，而p27（Kip1）同时与Cks1和Skp2结合。磷酸化的p27（Kip1）的Thr187侧链被Cks1的磷酸结合位点识别，而不变的Glu185侧链插入Skp2和Cks1之间的界面，与两者相互作用。结构和生化数据支持Cdk2-cyclin A促进p27（Kip1）募集到SCF(Skp2)-Cks1复合物的模型。该研究结果发表在《分子细胞》杂志上，并在PDB （1AST）中沉积了结构。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. 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. This work was published in Molecular Cell and the structure deposited in the PDB (1AST).