7B5L

Ubiquitin ligation to F-box protein substrates by SCF-RBR E3-E3 super-assembly: NEDD8-CUL1-RBX1-SKP1-SKP2-CKSHS1-Cyclin A-CDK2-p27-UBE2L3~Ub~ARIH1. Transition State 1

7B5L の概要

• エントリーDOI: 10.2210/pdb7b5l/pdb
• EMDBエントリー: 12004 12005 12006 12007 12037
• 分子名称: Cullin-1, Cyclin-dependent kinase 2, Cyclin-A2, ... (14 entities in total)
• 機能のキーワード: ubiquitin, ubiquitin ligase, e3 ligase, f-box protein, rbr ligase, cullin-ring-ligase, crl, scf, nedd8, post-translational modification, ubiquitylation, ligase
• 由来する生物種: Homo sapiens (Human); 詳細
• タンパク質・核酸の鎖数: 12
• 化学式量合計: 382217.52

構造登録者

Horn-Ghetko, D.,Prabu, J.R.,Schulman, B.A. (登録日: 2020-12-04, 公開日: 2021-02-10, 最終更新日: 2025-07-02)

主引用文献

Horn-Ghetko, D.,Krist, D.T.,Prabu, J.R.,Baek, K.,Mulder, M.P.C.,Klugel, M.,Scott, D.C.,Ovaa, H.,Kleiger, G.,Schulman, B.A.
Ubiquitin ligation to F-box protein targets by SCF-RBR E3-E3 super-assembly.
Nature, 590:671-676, 2021

PubMed Abstract: E3 ligases are typically classified by hallmark domains such as RING and RBR, which are thought to specify unique catalytic mechanisms of ubiquitin transfer to recruited substrates. However, rather than functioning individually, many neddylated cullin-RING E3 ligases (CRLs) and RBR-type E3 ligases in the ARIH family-which together account for nearly half of all ubiquitin ligases in humans-form E3-E3 super-assemblies. Here, by studying CRLs in the SKP1-CUL1-F-box (SCF) family, we show how neddylated SCF ligases and ARIH1 (an RBR-type E3 ligase) co-evolved to ubiquitylate diverse substrates presented on various F-box proteins. We developed activity-based chemical probes that enabled cryo-electron microscopy visualization of steps in E3-E3 ubiquitylation, initiating with ubiquitin linked to the E2 enzyme UBE2L3, then transferred to the catalytic cysteine of ARIH1, and culminating in ubiquitin linkage to a substrate bound to the SCF E3 ligase. The E3-E3 mechanism places the ubiquitin-linked active site of ARIH1 adjacent to substrates bound to F-box proteins (for example, substrates with folded structures or limited length) that are incompatible with previously described conventional RING E3-only mechanisms. The versatile E3-E3 super-assembly may therefore underlie widespread ubiquitylation.

PubMed: 33536622
DOI: 10.1038/s41586-021-03197-9

実験手法

ELECTRON MICROSCOPY (3.8 Å)