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Allosteric activation of the RNF146 ubiquitin ligase by a poly(ADP-ribosyl)ation signal | |
2015 | |
发表期刊 | NATURE |
ISSN | 0028-0836 |
EISSN | 1476-4687 |
卷号 | 517期号:7533页码:223-U275 |
发表状态 | 已发表 |
DOI | 10.1038/nature13826 |
摘要 | Protein poly(ADP-ribosyl)ation (PARylation) has a role in diverse cellular processes such as DNA repair, transcription, Wnt signalling, andcell death(1-6). Recent studies have shown that PARylation can serve as a signal for the polyubiquitination and degradation of several crucial regulatory proteins, including Axin and 3BP2 (refs 7-9). The RING-type E3 ubiquitin ligase RNF146 (also known as Iduna) is responsible for PARylation-dependent ubiquitination (PARdU)(10-12). Here we provide a structural basis for RNF146-catalysed PARdU and how PARdU specificity is achieved. First, we show that iso-ADP-ribose (iso-ADPr), the smallest internal poly(ADP-ribose) (PAR) structural unit, binds between the WWE and RING domains of RNF146 and functions as an allosteric signal that switches the RING domain from a catalytically inactive state to an active one. In the absence of PAR, the RING domain is unable to bind and activate a ubiquitin-conjugating enzyme (E2) efficiently. Binding of PAR or iso-ADPr induces a major conformational change that creates a functional RING structure. Thus, RNF146 represents a new mechanistic class of RING E3 ligases, the activities of which are regulated by non-covalent ligand binding, and that may provide a template for designing inducible protein-degradation systems. Second, we find that RNF146 directly interacts with the PAR polymerase tankyrase (TNKS). Disruption of the RNF146-TNKS interaction inhibits turnover of the substrate Axin in cells. Thus, both substrate PARylation and PARdU are catalysed by enzymes within the same protein complex, and PARdU substrate specificity may be primarily determined by the substrate-TNKS interaction. We propose that the maintenance of unliganded RNF146 in an inactive state may serve to maintain the stability of the RNF146-TNKS complex, which in turn regulates the homeostasis of PARdU activity in the cell. |
URL | 查看原文 |
收录类别 | SCI |
WOS研究方向 | Science & Technology - Other Topics |
WOS类目 | Multidisciplinary Sciences |
WOS记录号 | WOS:000347477600041 |
WOS关键词 | CRYSTAL-STRUCTURE ; STRUCTURAL BASIS ; COMPLEX REVEALS ; E3 LIGASE ; RECOGNITION ; MECHANISM ; AXIN ; PROTEINS ; INSIGHTS ; SYSTEM |
原始文献类型 | Article |
引用统计 | |
文献类型 | 期刊论文 |
条目标识符 | https://kms.shanghaitech.edu.cn/handle/2MSLDSTB/120352 |
专题 | 个人在本单位外知识产出 |
共同第一作者 | Wang, Zhizhi |
通讯作者 | Klevit, Rachel E.; Xu, Wenqing |
作者单位 | 1.Univ Washington, Dept Biochem, Seattle, WA 98195 USA 2.Univ Washington, Dept Biol Struct, Seattle, WA 98195 USA 3.Novartis Inst Biomed Res, Cambridge, MA 02139 USA |
推荐引用方式 GB/T 7714 | DaRosa, Paul A.,Wang, Zhizhi,Jiang, Xiaomo,et al. Allosteric activation of the RNF146 ubiquitin ligase by a poly(ADP-ribosyl)ation signal[J]. NATURE,2015,517(7533):223-U275. |
APA | DaRosa, Paul A..,Wang, Zhizhi.,Jiang, Xiaomo.,Pruneda, Jonathan N..,Cong, Feng.,...&Xu, Wenqing.(2015).Allosteric activation of the RNF146 ubiquitin ligase by a poly(ADP-ribosyl)ation signal.NATURE,517(7533),223-U275. |
MLA | DaRosa, Paul A.,et al."Allosteric activation of the RNF146 ubiquitin ligase by a poly(ADP-ribosyl)ation signal".NATURE 517.7533(2015):223-U275. |
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