Multimodal activation of the ubiquitin ligase SCF by Nedd8 conjugation.
Multimodal activation of the ubiquitin ligase SCF by Nedd8 conjugation.
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DOI：
10.1016/j.molcel.2008.08.021
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发表时间：
2008-10-10
期刊：
影响因子：
16
通讯作者：
Deshaies, Raymond J.
中科院分区：
文献类型：
--
作者：
Saha, Anjanabha;Deshaies, Raymond J.
泛素样蛋白Nedd 8与cullin的缀合（即neddylation）对于cullin-RING泛素连接酶（CRL）的功能是必不可少的。在这里，我们表明neddylation刺激的泛素缀合酶（E2）与泛素（E2~Ub）酯化的招聘，帮助E2和SCF结合的底物之间的约50碱基的差距，使他们的反应，并促进E2的活性位点的酰胺键的形成。总之，这些作用有力地刺激泛素转移到底物。我们建议，启动子泛素跨越差距，和neddylation的影响，随后的泛素转移的E2 Cdc 34产生的E2招聘和增强酰胺键形成的E2活性位点。neddylation的组合效应大大增加了底物分子在与CRL的单次接触中获得≥4个泛素的可能性。Nedd 8缀合的令人惊讶的不同效果强调了CRL调节的复杂性，并表明用泛素或泛素样蛋白修饰其他泛素连接酶可能同样具有重要的功能后果。
Conjugation of ubiquitin-like protein Nedd8 to cullin (i.e. neddylation) is essential for the function of cullin-RING ubiquitin ligases (CRLs). Here we show that neddylation stimulates recruitment of ubiquitin-conjugating enzyme (E2) esterified with ubiquitin (E2~Ub), helps bridge the ~50 Å gap between E2 and substrate bound to SCF to enable their reaction, and facilitates formation of amide bonds in E2's active site. Together, these effects potently stimulate transfer of ubiquitin to substrate. We propose that the initiator ubiquitin spans the gap, and the impact of neddylation on transfer of subsequent ubiquitins by the E2 Cdc34 arises from improved E2 recruitment and enhanced amide bond formation in the E2 active site. The combined effects of neddylation greatly enhance the probability that a substrate molecule acquires ≥4 ubiquitins in a single encounter with a CRL. The surprisingly diverse effects of Nedd8 conjugation underscore the complexity of CRL regulation and suggest that modification of other ubiquitin ligases with ubiquitin or ubiquitin-like proteins may likewise have major functional consequences.
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