7OD1

Crystal structure of RBR ubiquitin ligase ARIH2

7OD1 の概要

• エントリーDOI: 10.2210/pdb7od1/pdb
• 分子名称: E3 ubiquitin-protein ligase ARIH2, ZINC ION (3 entities in total)
• 機能のキーワード: triad1, arih2, rbr, ubiquitin, e3 ligase, ligase
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 116572.60

構造登録者

Kostrhon, S.P.,Prabu, J.R.,Schulman, B.A. (登録日: 2021-04-28, 公開日: 2021-09-15, 最終更新日: 2024-06-19)

主引用文献

Kostrhon, S.,Prabu, J.R.,Baek, K.,Horn-Ghetko, D.,von Gronau, S.,Klugel, M.,Basquin, J.,Alpi, A.F.,Schulman, B.A.
CUL5-ARIH2 E3-E3 ubiquitin ligase structure reveals cullin-specific NEDD8 activation.
Nat.Chem.Biol., 17:1075-1083, 2021

PubMed Abstract: An emerging mechanism of ubiquitylation involves partnering of two distinct E3 ligases. In the best-characterized E3-E3 pathways, ARIH-family RING-between-RING (RBR) E3s ligate ubiquitin to substrates of neddylated cullin-RING E3s. The E3 ARIH2 has been implicated in ubiquitylation of substrates of neddylated CUL5-RBX2-based E3s, including APOBEC3-family substrates of the host E3 hijacked by HIV-1 virion infectivity factor (Vif). However, the structural mechanisms remained elusive. Here structural and biochemical analyses reveal distinctive ARIH2 autoinhibition, and activation on assembly with neddylated CUL5-RBX2. Comparison to structures of E3-E3 assemblies comprising ARIH1 and neddylated CUL1-RBX1-based E3s shows cullin-specific regulation by NEDD8. Whereas CUL1-linked NEDD8 directly recruits ARIH1, CUL5-linked NEDD8 does not bind ARIH2. Instead, the data reveal an allosteric mechanism. NEDD8 uniquely contacts covalently linked CUL5, and elicits structural rearrangements that unveil cryptic ARIH2-binding sites. The data reveal how a ubiquitin-like protein induces protein-protein interactions indirectly, through allostery. Allosteric specificity of ubiquitin-like protein modifications may offer opportunities for therapeutic targeting.

PubMed: 34518685
DOI: 10.1038/s41589-021-00858-8

実験手法

X-RAY DIFFRACTION (2.45 Å)