| Structural highlights
Disease
SODC_HUMAN Defects in SOD1 are the cause of amyotrophic lateral sclerosis type 1 (ALS1) [MIM:105400. ALS1 is a familial form of amyotrophic lateral sclerosis, a neurodegenerative disorder affecting upper and lower motor neurons and resulting in fatal paralysis. Sensory abnormalities are absent. Death usually occurs within 2 to 5 years. The etiology of amyotrophic lateral sclerosis is likely to be multifactorial, involving both genetic and environmental factors. The disease is inherited in 5-10% of cases leading to familial forms.[1] [2] [3] [4] [5] [6] [7] [8] [:][9] [10] [11] [12] [13] [14] [15] [16] [17] [18] [19] [20] [21] [22] [23] [24] [25] [26] [27] [28] [29] [30] [31] [32] [33] [34] [35] [36] [37] [38] [39] [40] [41] [42] [43] [44] [45]
Function
SODC_HUMAN Destroys radicals which are normally produced within the cells and which are toxic to biological systems.
Publication Abstract from PubMed
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.
Structural analysis of the overoxidized Cu/Zn-superoxide dismutase in ROS-induced ALS filament formation.,Baek Y, Woo TG, Ahn J, Lee D, Kwon Y, Park BJ, Ha NC Commun Biol. 2022 Oct 12;5(1):1085. doi: 10.1038/s42003-022-04017-0. PMID:36224351[46]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
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- ↑ Baek Y, Woo TG, Ahn J, Lee D, Kwon Y, Park BJ, Ha NC. Structural analysis of the overoxidized Cu/Zn-superoxide dismutase in ROS-induced ALS filament formation. Commun Biol. 2022 Oct 12;5(1):1085. doi: 10.1038/s42003-022-04017-0. PMID:36224351 doi:https://dx.doi.org/10.1038/s42003-022-04017-0
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