Regulation of ubiquitin-binding proteins by monoubiquitination
Regulation of ubiquitin-binding proteins by monoubiquitination
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DOI：
10.1038/ncb1354
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发表时间：
2006-02-01
影响因子：
21.3
通讯作者：
Dikic, I
中科院分区：
文献类型：
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作者：
Hoeller, D;Crosetto, N;Dikic, I
含有泛素结合域（UBDs）的蛋白质与泛素化靶点相互作用，并调节多种生物过程，包括内吞作用、信号转导、转录和DNA修复（1-3）。许多含有ubd的蛋白质本身也是单泛素化的，但这种修饰的功能作用和机制尚不清楚。在这里，我们证明单泛素化的内吞蛋白Sts1， Sts2， Eps15和Hrs导致泛素与其UBDs之间的分子内相互作用，从而阻止它们反式结合到泛素化的靶标上。这些蛋白质的永久单泛素化，由泛素与它们的羧基端融合所模拟，削弱了它们调节泛素化受体运输的能力。此外，我们绘制了Sts2的体内单泛素化位点，并证明其突变增强了Sts2介导的表皮生长因子受体下调的作用。我们认为泛素结合蛋白的单泛素化抑制了它们与体内泛素化靶标的结合和控制功能的能力。
Proteins containing ubiquitin-binding domains (UBDs) interact with ubiquitinated targets and regulate diverse biological processes, including endocytosis, signal transduction, transcription and DNA repair(1-3). Many of the UBD-containing proteins are also themselves monoubiquitinated, but the functional role and the mechanisms that underlie this modification are less well understood. Here, we demonstrate that monoubiquitination of the endocytic proteins Sts1, Sts2, Eps15 and Hrs results in intramolecular interactions between ubiquitin and their UBDs, thereby preventing them from binding in trans to ubiquitinated targets. Permanent monoubiquitination of these proteins, mimicked by the fusion of ubiquitin to their carboxyl termini, impairs their ability to regulate trafficking of ubiquitinated receptors. Moreover, we mapped the in vivo monoubiquitination site in Sts2 and demonstrated that its mutation enhances the Sts2-mediated effects of epidermal-growth-factor-receptor downregulation. We propose that monoubiquitination of ubiquitin-binding proteins inhibits their capacity to bind to and control the functions of ubiquitinated targets in vivo.