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首页> 外文期刊>Cellular Signalling >Characterization of cullin-based E3 ubiquitin ligases in intact mammalian cells - Evidence for cullin dimerization
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Characterization of cullin-based E3 ubiquitin ligases in intact mammalian cells - Evidence for cullin dimerization

机译：完整哺乳动物细胞中基于cullin的E3泛素连接酶的特征-cullin二聚化的证据

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摘要

Cullin-based E3 ligases are a large family of ubiquitin ligases with diverse cellular functions. They are composed of one of six mammalian cullin homologues, the Ring finger containing protein Roc1/Rbx1 and cullin homologue-specific adapter and substrate recognition subunits. To be active, cullin-based ligases require the covalent modification of a conserved lysine residue in the cullin protein with the ubiquitin-like protein Nedd8. To characterize this family of E3 ligases in intact cells, we generated a cell line with tetracycline-inducible expression of a dominant-negative mutant of the Nedd8-conjugating enzyme Ubc12, a reported inhibitor of cullin neddylation. Using this cell line, we demonstrate that the substrate recognition subunit Skp2 and the adaptor protein Skp1 are subject to Ubc12-dependent autoubiquitination and degradation. In contrast, cullin protein stability is not regulated by neddylation in mammalian cells. We also provide evidence that Cull and Cul3, as well as their associated substrate recognition subunits Skp2 and Keap1, respectively, homooligomerize in intact cells, suggesting that cullin-based ligases are dimeric. Cul3, but not Cul1 homooligomerization is dependent on substrate recognition subunit dimer formation. As shown for other E3 ubiquitin ligases, dimerization may play a role in regulating the activity of cullin-based E3 ligases. (c) 2006 Elsevier Inc. All rights reserved.
机译：基于Cullin的E3连接酶是泛素连接酶的一大家族，具有多种细胞功能。它们由六个哺乳动物cullin同源物之一组成，其中无名指含有蛋白Roc1 / Rbx1和cullin同源物特异性衔接子以及底物识别亚基。为了具有活性，基于cullin的连接酶需要使用泛素样蛋白Nedd8对cullin蛋白中保守的赖氨酸残基进行共价修饰。为了表征完整细胞中这个E3连接酶家族，我们生成了具有Nedd8缀合酶Ubc12（据报道的cullin醛基化抑制剂）的显性负突变体的四环素诱导表达的细胞系。使用此细胞系，我们证明底物识别亚基Skp2和衔接蛋白Skp1受到Ubc12依赖的自体泛素化和降解。相反，在哺乳动物细胞中，cullin蛋白的稳定性不受糊精作用的调节。我们还提供证据表明，Cull和Cul3以及它们相关的底物识别亚基Skp2和Keap1分别在完整细胞中均聚，表明基于cullin的连接酶是二聚体。 Cul3，但不是Cul1均聚取决于底物识别亚基二聚体的形成。如其他E3泛素连接酶所示，二聚化可能在调节基于cullin的E3连接酶的活性中起作用。 （c）2006 Elsevier Inc.保留所有权利。

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