8H3F

Cryo-EM Structure of the KBTBD2-CRL3-CSN complex

8H3F の概要

• エントリーDOI: 10.2210/pdb8h3f/pdb
• EMDBエントリー: 34467
• 分子名称: COP9 signalosome complex subunit 5, E3 ubiquitin-protein ligase RBX1, Cullin-3, ... (12 entities in total)
• 機能のキーワード: ligase, complex
• 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: 578452.85

構造登録者

Hu, Y.,Mao, Q.,Chen, Z.,Sun, L. (登録日: 2022-10-08, 公開日: 2023-10-11, 最終更新日: 2024-03-20)

主引用文献

Hu, Y.,Zhang, Z.,Mao, Q.,Zhang, X.,Hao, A.,Xun, Y.,Wang, Y.,Han, L.,Zhan, W.,Liu, Q.,Yin, Y.,Peng, C.,Moresco, E.M.Y.,Chen, Z.,Beutler, B.,Sun, L.
Dynamic molecular architecture and substrate recruitment of cullin3-RING E3 ligase CRL3 KBTBD2.
Nat.Struct.Mol.Biol., 31:336-350, 2024

PubMed Abstract: Phosphatidylinositol 3-kinase α, a heterodimer of catalytic p110α and one of five regulatory subunits, mediates insulin- and insulin like growth factor-signaling and, frequently, oncogenesis. Cellular levels of the regulatory p85α subunit are tightly controlled by regulated proteasomal degradation. In adipose tissue and growth plates, failure of K48-linked p85α ubiquitination causes diabetes, lipodystrophy and dwarfism in mice, as in humans with SHORT syndrome. Here we elucidated the structures of the key ubiquitin ligase complexes regulating p85α availability. Specificity is provided by the substrate receptor KBTBD2, which recruits p85α to the cullin3-RING E3 ubiquitin ligase (CRL3). CRL3 forms multimers, which disassemble into dimers upon substrate binding (CRL3-p85α) and/or neddylation by the activator NEDD8 (CRL3~N8), leading to p85α ubiquitination and degradation. Deactivation involves dissociation of NEDD8 mediated by the COP9 signalosome and displacement of KBTBD2 by the inhibitor CAND1. The hereby identified structural basis of p85α regulation opens the way to better understanding disturbances of glucose regulation, growth and cancer.

PubMed: 38332366
DOI: 10.1038/s41594-023-01182-6

実験手法

ELECTRON MICROSCOPY (6.73 Å)