4QPL

Crystal structure of RNF146(RING-WWE)/UbcH5a/iso-ADPr complex

4QPL の概要

• エントリーDOI: 10.2210/pdb4qpl/pdb
• 分子名称: E3 ubiquitin-protein ligase RNF146, Ubiquitin-conjugating enzyme E2 D1, 2'-O-(5-O-phosphono-alpha-D-ribofuranosyl)adenosine 5'-(dihydrogen phosphate), ... (5 entities in total)
• 機能のキーワード: protein poly(adp-ribosy)lation, ubiquitination, e2/e3 ubiquitin ligase, wnt signaling, rnf146, ubch5a, iso-adpr, ligase
• 由来する生物種: Mus musculus (mouse); 詳細
• 細胞内の位置: Cytoplasm, cytosol : Q9CZW6; Cytoplasm : P51668
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 72139.37

構造登録者

Wang, Z.,DaRosa, P.A.,Klevit, R.E.,Xu, W. (登録日: 2014-06-23, 公開日: 2014-10-15, 最終更新日: 2024-02-28)

主引用文献

DaRosa, P.A.,Wang, Z.,Jiang, X.,Pruneda, J.N.,Cong, F.,Klevit, R.E.,Xu, W.
Allosteric activation of the RNF146 ubiquitin ligase by a poly(ADP-ribosyl)ation signal.
Nature, 517:223-226, 2015

PubMed Abstract: Protein poly(ADP-ribosyl)ation (PARylation) has a role in diverse cellular processes such as DNA repair, transcription, Wnt signalling, and cell death. 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, 8, 9). The RING-type E3 ubiquitin ligase RNF146 (also known as Iduna) is responsible for PARylation-dependent ubiquitination (PARdU). 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.

PubMed: 25327252
DOI: 10.1038/nature13826

実験手法

X-RAY DIFFRACTION (1.9 Å)