Fbw7/hCDC4 dimerization regulates its substrate interactions.
Fbw7/hCDC4 dimerization regulates its substrate interactions.
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DOI：
10.1186/1747-1028-2-7
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发表时间：
2007-02-13
期刊：
影响因子：
2.3
通讯作者：
Clurman, Bruce E
中科院分区：
文献类型：
--
作者：
Welcker, Markus;Clurman, Bruce E
Fbw 7泛素连接酶促进几种重要癌基因的快速降解，如细胞周期蛋白E、c-Myc、c-Jun和Notch。Fbw 7的两个裂殖酵母同源物，pop 1和pop 2，先前已经显示出二聚化。在这项研究中，我们询问Fbw 7是否也可以二聚化以及二聚化如何影响Fbw 7功能。我们发现Fbw 7通过其F-box上游的结构域有效地与自身结合。我们进一步表明，二聚化是必不可少的Fbw 7与细胞周期蛋白E T380磷酸降解决定子的稳定相互作用。令人惊讶的是，对二聚化的需求可以通过在+4位置（S384）处的该磷酸-降解决定子的额外磷酸化来抑制，这产生了对单体Fbw 7具有更高亲和力的结合位点。因此，Fbw 7途径对细胞周期蛋白E的降解可以通过Fbw 7二聚化或T380磷酸化降解决定子的过度磷酸化来有条件地调节。不能在其磷酸降解决定子中容纳额外的磷酸或在+4位置不提供带负电荷的氨基酸的其他底物可能绝对依赖于Fbw 7二聚化用于其周转。我们的研究结果表明，Fbw 7对底物相互作用和营业额有额外的调节作用。
The Fbw7 ubiquitin ligase promotes the rapid degradation of several important oncogenes, such as cyclin E, c-Myc, c-Jun, and Notch. The two fission yeast homologs of Fbw7, pop1 and pop2, have previously been shown to dimerize. In this study, we asked whether Fbw7 can also dimerize and how dimerization affects Fbw7 function. We found that Fbw7 binds efficiently to itself through a domain just upstream of its F-box. We further show that dimerization is essential for the stable interaction of Fbw7 with the cyclin E T380 phospho-degron. Surprisingly, the requirement for dimerization can be suppressed by an additional phosphorylation of this phospho-degron at the +4 position (S384), which creates a binding site with higher affinity for monomeric Fbw7. Degradation of cyclin E by the Fbw7 pathway can, thus, be conditionally regulated either by Fbw7 dimerization or by hyperphosphorylation of the T380 phospho-degron. Other substrates, which cannot accommodate an extra phosphate in their phospho-degrons, or which don't provide a negatively charged amino acid in the +4 position, may be absolutely dependent on Fbw7 dimerization for their turnover. Our results point to an additional level of regulation for substrate interaction and turnover by Fbw7.