8PJN

Catalytic module of human CTLH E3 ligase bound to multiphosphorylated UBE2H~ubiquitin

8PJN の概要

• エントリーDOI: 10.2210/pdb8pjn/pdb
• 関連するPDBエントリー: 8PMQ
• EMDBエントリー: 17705 17706 17707 17709 17710 17713 17715 17716 17717 17764
• 分子名称: E3 ubiquitin-protein transferase RMND5A, Ubiquitin-conjugating enzyme E2 H, E3 ubiquitin-protein transferase MAEA, ... (5 entities in total)
• 機能のキーワード: e3 ubiquitin ligase, e2 ubiquitin-conjugating enzyme, phosphorylation, ctlh, gid, ube2h, ligase
• 由来する生物種: Homo sapiens (human); 詳細
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 119368.42

構造登録者

Chrustowicz, J.,Sherpa, D.,Prabu, R.J.,Schulman, B.A. (登録日: 2023-06-23, 公開日: 2024-01-03, 最終更新日: 2025-07-09)

主引用文献

Chrustowicz, J.,Sherpa, D.,Li, J.,Langlois, C.R.,Papadopoulou, E.C.,Vu, D.T.,Hehl, L.A.,Karayel, O.,Beier, V.,von Gronau, S.,Muller, J.,Prabu, J.R.,Mann, M.,Kleiger, G.,Alpi, A.F.,Schulman, B.A.
Multisite phosphorylation dictates selective E2-E3 pairing as revealed by Ubc8/UBE2H-GID/CTLH assemblies.
Mol.Cell, 84:293-, 2024

PubMed Abstract: Ubiquitylation is catalyzed by coordinated actions of E3 and E2 enzymes. Molecular principles governing many important E3-E2 partnerships remain unknown, including those for RING-family GID/CTLH E3 ubiquitin ligases and their dedicated E2, Ubc8/UBE2H (yeast/human nomenclature). GID/CTLH-Ubc8/UBE2H-mediated ubiquitylation regulates biological processes ranging from yeast metabolic signaling to human development. Here, cryoelectron microscopy (cryo-EM), biochemistry, and cell biology reveal this exquisitely specific E3-E2 pairing through an unconventional catalytic assembly and auxiliary interactions 70-100 Å away, mediated by E2 multisite phosphorylation. Rather than dynamic polyelectrostatic interactions reported for other ubiquitylation complexes, multiple Ubc8/UBE2H phosphorylation sites within acidic CK2-targeted sequences specifically anchor the E2 C termini to E3 basic patches. Positions of phospho-dependent interactions relative to the catalytic domains correlate across evolution. Overall, our data show that phosphorylation-dependent multivalency establishes a specific E3-E2 partnership, is antagonistic with dephosphorylation, rigidifies the catalytic centers within a flexing GID E3-substrate assembly, and facilitates substrate collision with ubiquitylation active sites.

PubMed: 38113892
DOI: 10.1016/j.molcel.2023.11.027

実験手法

ELECTRON MICROSCOPY (3.4 Å)