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

SCF(SKP2) 泛素连接酶对 P27(KIP1) 的 CKS1 依赖性识别

• 批准号: 7369532
• 负责人: NIKOLA P PAVLETICH
• 金额: $ 0.18万
• 依托单位: CORNELL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-06-01 至 2007-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7369532
• 关键词: CKS1; DEPENDENT; RECOGNITION; P27; KIP1

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).

该子项目是利用 NIH/NCRR 资助的中心拨款提供的资源的众多研究子项目之一。子项目和研究者 (PI) 可能已从另一个 NIH 来源获得主要资金，因此可以在其他 CRISP 条目中出现。列出的机构是中心的机构，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展中发挥着核心作用，p27 (Kip1) 降解的增强与许多常见癌症有关。 p27(Kip1) 的蛋白水解由 Thr187 磷酸化触发，从而导致 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) 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 (LRR) 结构域和 C 末端尾部结合，而 p27(Kip1) 与两个 Cks1 结合和Skp2。 p27(Kip1) 的磷酸化 Thr187 侧链被 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所提出的模型，即 Cdk2-cyclin A 有助于将 p27(Kip1) 招募到 SCF(Skp2)-Cks1 复合物中。 这项工作发表在《Molecular Cell》杂志上，结构存放在 PDB (1AST) 中。