7FB6

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

Summary for 7FB6

• Entry DOI: 10.2210/pdb7fb6/pdb
• Descriptor: Superoxide dismutase [Cu-Zn], ZINC ION, COPPER (II) ION, ... (5 entities in total)
• Functional Keywords: superoxide, oxidation, metalloprotein, hydrogen peroxide, filament, als, oxidoreductase
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 2
• Total formula weight: 33786.28

Authors

Baek, Y.,Ha, N.-C. (deposition date: 2021-07-08, release date: 2022-10-12, Last modification date: 2024-11-13)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (1.8 Å)