Molecular Mechanism of COP9 Signalosome Activity

描述(由申请人提供)： COP9信号体(CSN)是一个保守的复合体，参与泛素-蛋白酶体介导的蛋白质降解。最近观察到CSN与含有cullin的E3泛素连接酶有物理上的联系，并且对泛素样NEDD8结合的cullins具有去动力活性。去动力和去动力循环对于泛素蛋白酶体系统调节蛋白质降解是重要的；然而，动力和去动力在细胞功能中的确切作用尚不清楚。为了阐明去核化和去去核化的生理后果，我建议使用拟南芥作为我的模型系统。将产生脱氧活性有缺陷但保持完整CSN复合体的突变菌株，并将它们的生化和发育特性与CSN缺失突变株和野生型进行比较。这些突变体将是：催化脱染缺陷，或在CSN与所有基于cullin的泛素连接酶或特定的包含cullin1的E3连接酶之间的相互作用中存在缺陷。这些研究将为CSN调节泛素化和蛋白质降解的机制提供关键的见解。

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.