Structure of a Fbw7-Skp1-cyclin E complex: Multisite-phosphorylated substrate recognition by SCF ubiquitin ligases
Structure of a Fbw7-Skp1-cyclin E complex: Multisite-phosphorylated substrate recognition by SCF ubiquitin ligases
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DOI：
10.1016/j.molcel.2007.02.022
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发表时间：
2007-04-13
期刊：
影响因子：
16
通讯作者：
Pavletich, Nikola P.
中科院分区：
文献类型：
--
作者：
Hao, Bing;Oehlmann, Stephanie;Pavletich, Nikola P.
泛素介导的细胞周期蛋白E的蛋白水解在细胞周期进程中起着重要作用，细胞周期蛋白E的积累是癌症中的常见事件。细胞周期蛋白E降解由多位点磷酸化触发，其诱导与SCFFbw 7泛素连接酶复合物结合。Skp 1-Fbw 7复合物结合到细胞周期蛋白E肽的结构鉴定了双磷酸化的pThr 380/pSer 384细胞周期蛋白E基序作为最佳的、高亲和力的降解决定子和单磷酸化的pThr 62基序作为低亲和力的。生物化学数据表明，密切相关的酵母SCFCdC 4复合物识别的多位点磷酸化的Sic 1基板类似，并确定三个双磷酸化的Sic 1降解决定子，每个能够与两个Cdc 4磷酸结合位点的高亲和力相互作用。Fbw 7和Cdc 4二聚化、Fbw 7二聚化增强体内弱相关细胞周期蛋白E的转换以及Cdc 4二聚化增加Sic 1体外遍在化的速率和持续合成能力的发现提供了解释多个细胞周期蛋白E/Sic 1降解决定子的作用的模型。
The ubiquitin-mediated proteolysis of cyclin E plays a central role in cell-cycle progression, and cyclin E accumulation is a common event in cancer. Cyclin E degradation is triggered by multisite phosphorylation, which induces binding to the SCFFbw7 ubiquitin ligase complex. Structures of the Skp1-Fbw7 complex bound to cyclin E peptides identify a doubly phosphorylated pThr380/pSer384 cyclin E motif as an optimal, high-affinity degron and a singly phosphorylated pThr62 motif as a low-affinity one. Biochemical data indicate that the closely related yeast SCFCdC4 complex recognizes the multisite phosphorylated Sic1 substrate similarly and identify three doubly phosphorylated Sic1 degrons, each capable of high-affinity interactions with two Cdc4 phosphate binding sites. A model that explains the role of multiple cyclin E/Sic1 degrons is provided by the findings that Fbw7 and Cdc4 dimerize, that Fbw7 dimerization enhances the turnover of a weakly associated cyclin E in vivo, and that Cdc4 dimerization increases the rate and processivity of Sic1 ubiquitination in vitro.