Molecular Mechanism of COP9 Signalosome Activity

描述（由申请人提供）： COP 9信号体（CSN）是一种保守的复合物，参与泛素-蛋白酶体介导的蛋白质降解。最近，已经观察到CSN与含有cullin的E3泛素连接酶物理相关，并且对泛素样NEDD 8缀合cullin具有去内酰化活性。neddylation和deneddylation的循环对于泛素蛋白酶体系统调节的蛋白质降解是重要的;然而，neddylation和deneddylation在细胞功能中的确切作用尚不清楚。为了阐明neddylation和deneddylation的生理后果，我建议使用拟南芥作为我的模式系统。将创建去内酰化活性缺陷但保持完整CSN复合物的突变菌株，并将其生化和发育特性与csn无效突变体和野生型进行比较。 这些突变体将是：去卷曲化催化缺陷或CSN与所有基于cullin的泛素连接酶或特定亚类、含cullin 1的E3连接酶之间的相互作用缺陷。这些研究将为深入了解CSN在调节泛素化和蛋白质降解中的作用机制提供重要的参考。

DESCRIPTION (provided by applicant): The COP9 signalosome (CSN) is a conserved complex that is involved in ubiquitin-proteasome mediated protein degradation. Recently it has been observed that the CSN is physically associated with cullin-containing E3 ubiquitin ligases and possesses a deneddylation activity for the ubiquitin-like NEDD8 conjugated cullins. Cycles of neddylation and deneddylation are important for regulated protein degradation by the ubiquitin proteasome system; however, the precise role of the neddylation and deneddylation in cell function is unclear. In order to elucidate the physiological consequences of neddylation and deneddylation, I propose to use Arabidopsis as my model system. Mutant strains will be created that are defective for deneddylation activity but maintain an intact CSN complex, and their biochemical and developmental properties will be compared to csn null mutants and wild type. These mutants will be: catalytically defective for deneddylation or defective in the interaction between the CSN and either all cullin-based ubiquitin ligases or a specific subset, cullin1-containing E3 ligases. These studies will provide critical insights toward the mechanism of CSN function in regulating ubiquitylation and protein degradation.