7FB6

C57D/C146D mutant of Human Cu, Zn Superoxide Dismutase (SOD1)

7FB6 の概要

• エントリーDOI: 10.2210/pdb7fb6/pdb
• 分子名称: Superoxide dismutase [Cu-Zn], ZINC ION, COPPER (II) ION, ... (5 entities in total)
• 機能のキーワード: superoxide, oxidation, metalloprotein, hydrogen peroxide, filament, als, oxidoreductase
• 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: 33786.28

構造登録者

Baek, Y.,Ha, N.-C. (登録日: 2021-07-08, 公開日: 2022-10-12, 最終更新日: 2024-11-13)

主引用文献

Baek, Y.,Woo, T.G.,Ahn, J.,Lee, D.,Kwon, Y.,Park, B.J.,Ha, N.C.
Structural analysis of the overoxidized Cu/Zn-superoxide dismutase in ROS-induced ALS filament formation.
Commun Biol, 5:1085-1085, 2022

PubMed Abstract: Eukaryotic Cu, Zn-superoxide dismutase (SOD1) is primarily responsible for cytotoxic filament formation in amyotrophic lateral sclerosis (ALS) neurons. Two cysteine residues in SOD1 form an intramolecular disulfide bond. This study aims to explore the molecular mechanism of SOD1 filament formation by cysteine overoxidation in sporadic ALS (sALS). In this study, we determined the crystal structure of the double mutant (C57D/C146D) SOD1 that mimics the overoxidation of the disulfide-forming cysteine residues. The structure revealed the open and relaxed conformation of loop IV containing the mutated Asp57. The double mutant SOD1 produced more contagious filaments than wild-type protein, promoting filament formation of the wild-type SOD1 proteins. Importantly, we further found that HOCl treatment to the wild-type SOD1 proteins facilitated their filament formation. We propose a feasible mechanism for SOD1 filament formation in ALS from the wild-type SOD1, suggesting that overoxidized SOD1 is a triggering factor of sALS. Our findings extend our understanding of other neurodegenerative disorders associated with ROS stresses at the molecular level.

PubMed: 36224351
DOI: 10.1038/s42003-022-04017-0

実験手法

X-RAY DIFFRACTION (1.8 Å)