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

该子项目是利用NIH/NCRR资助的中心赠款提供的资源的许多研究子项目之一。子项目和研究者（PI）可能从另一个NIH来源获得了主要资金，因此可以在其他CRISP条目中表示。所列机构为中心，不一定是研究者所在机构。Cdk 2抑制剂p27（Kip 1）的泛素介导的蛋白水解在细胞周期进程中起着重要作用，p27（Kip 1）的降解增强与许多常见癌症相关。p27（Kip 1）的蛋白水解由Thr 187磷酸化触发，这导致SCF（Skp 2）（Skp 1-Cul 1-Rbx 1-Skp 2）泛素连接酶复合物的结合。与其他已知的SCF底物不同，p27（Kip 1）泛素化还需要辅助蛋白Cks 1。Skp 1-Skp 2-Cks 1复合物与p27（Kip 1）磷酸肽结合的晶体结构表明，Cks 1与Skp 2的富含亮氨酸重复序列（LRR）结构域和C-末端尾部结合，而p27（Kip 1）与Cks 1和Skp 2结合。磷酸化的Thr 187侧链的p27（Kip 1）是由Cks 1磷酸结合位点识别，而侧链的一个不变的Glu 185插入Skp 2和Cks 1之间的界面，与两者相互作用。结构和生化数据支持提出的模型，Cdk 2-细胞周期蛋白A有助于招募p27（Kip 1）的SCF（Skp 2）-Cks 1复合物。 这项工作发表在《分子细胞》上，结构存放在PDB（1AST）上。

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).