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

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 泛素介导的CDK2抑制蛋白p27(Kip1)的蛋白分解在细胞周期进程中起核心作用，p27(Kip1)的降解增强与许多常见癌症有关。蛋白水解酶p27(Kip1)由Thr187磷酸化引发，导致SCF(Skp2)(Skp1-Cul1-Rbx1-Skp2)泛素连接酶复合体的结合。与其他已知的SCF底物不同，p27(Kip1)泛素化还需要辅助蛋白Cks1。与p27(Kip1)磷酸肽结合的Skp1-Skp2-Cks1复合体的晶体结构表明，Cks1与Skp2的亮氨酸重复序列(LRR)结构域和C末端结合，而p27(Kip1)与Cks1和Skp2结合。P27(Kip1)的磷酸化Thr187侧链通过Cks1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有助于将p27(Kip1)募集到SCF(Skp2)-Cks1复合体的模型。 这项工作发表在《分子细胞》和《PDB中存放的结构》(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).