Structural basis for a reciprocal regulation between SCF and CSN.
Structural basis for a reciprocal regulation between SCF and CSN.
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DOI：
10.1016/j.celrep.2012.08.019
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发表时间：
2012-09-27
期刊：
影响因子：
8.8
通讯作者：
Morris EP
中科院分区：
文献类型：
--
作者：
Enchev RI;Scott DC;da Fonseca PC;Schreiber A;Monda JK;Schulman BA;Peter M;Morris EP
SCF(Skp1-Cul1-Fbox)E3连接酶通过连接泛素样蛋白Nedd8而被激活，而Neddylating COP9信号小体(CSN)逆转了泛素样蛋白Nedd8的激活。然而，CSN也通过未知的机制促进SCF底物的周转。通过生化和电子显微镜分析，我们确定了CSN与SCFSkp2/Cks1和SCFFbw7的分子模型，发现CSN封闭了SCF的两个功能部位--催化的Rbx1-Cul1 C-末端结构域和底物受体。事实上，CSN结合阻止了SCF与E2酶和泛素化底物的相互作用，并抑制了SCF催化的泛素链的形成，而不依赖于脱染作用。重要的是，除非泛素化底物的结合触发了SCF的解离和去化，否则CSN可以阻止结合的cullin的去化。综上所述，这些结果为相互调节如何使CSN对SCF组装状态敏感提供了一个模型，并抑制了具有催化活性的SCF，直到泛素化底物通过取代CSN来驱动自己的降解，从而促进了剔除和底物泛素化。
SCF (Skp1-Cul1-Fboxes) E3 ligases are activated by ligation to the ubiquitin-like protein Nedd8, which is reversed by the deneddylating Cop9 Signalosome (CSN). However, CSN also promotes SCF substrate turnover through unknown mechanisms. Through biochemical and electron microscopy analyses, we determined molecular models of CSN complexes with SCFSkp2/Cks1 and SCFFbw7 and found that CSN occludes both SCF functional sites – the catalytic Rbx1-Cul1 C-terminal domain and the substrate receptor. Indeed, CSN binding prevents SCF interactions with E2 enzymes and a ubiquitination substrate, and inhibits SCF-catalyzed ubiquitin chain formation independent of deneddylation. Importantly, CSN prevents neddylation of the bound cullin, unless binding of a ubiquitination substrate triggers SCF dissociation and neddylation. Taken together, the results provide a model for how reciprocal regulation sensitizes CSN to the SCF assembly state, and inhibits a catalytically-competent SCF until a ubiquitination substrate drives its own degradation by displacing CSN, thereby promoting cullin neddylation and substrate ubiquitination.
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