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Superoxide dismutase 1 (SOD1) trimer interactome from mouse brain, spinal cord, and muscle tissues

ABSTRACT: In this work, we aimed to discover the protein binding partners of SOD1 trimers in brain, spinal cord, and skeletal muscle of mice tissue lysate.

INSTRUMENT(S):

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Brain, Nerve Cord, Tibialis Anterior

SUBMITTER: Esther Choi

LAB HEAD: Nikolay V Dokholyan

PROVIDER: PXD050873 | Pride | 2025-10-06

REPOSITORIES: Pride

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			Action	DRS
	DZ_V83_3_75ng_Slot1-34_1_126.d.zip	Other
	Dokh_Choi_WT_GH2_Slot1-51_1_560.d.zip	Other
	Dokh_Choi_WT_HQ1_Slot1-50_1_559.d.zip	Other
	Dokh_EChoi_WT_GH2_half_Slot1-51_1_562.d.zip	Other
	Dokh_EChoi_WT_HQ1_half_Slot1-50_1_561.d.zip	Other

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Publications

Unveiling the double-edged sword: SOD1 trimers possess tissue-selective toxicity and bind septin-7 in motor neuron-like cells.

Choi Esther Sue ES Hnath Brianna B Sha Congzhou Mike CM Dokholyan Nikolay V NV

Structure (London, England : 1993) 20240828 10

Misfolded species of superoxide dismutase 1 (SOD1) are associated with increased death in amyotrophic lateral sclerosis (ALS) models compared to insoluble protein aggregates. The mechanism by which structurally independent SOD1 trimers cause cellular toxicity is unknown but may drive disease pathology. Here, we uncovered the SOD1 trimer interactome-a map of potential tissue-selective protein-binding partners in the brain, spinal cord, and skeletal muscle. We identified binding partners and key p ...[more]

PMID: 39208794

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Association of copper-zinc superoxide dismutase (SOD1) and manganese superoxide dismutase (SOD2) genes with nonsyndromic myelomeningocele.

Project description:A common and severe neural tube defect (NTD) phenotype, myelomeningocele (MM), results from the defective closure of the caudal end of the neural tube with herniation of the spinal cord and meninges through the vertebral column. The exact mechanisms for NTDs are unknown, but excessive oxidative stress, particularly in association with maternal diabetes, has been postulated as a mechanism for MM.The SNPlex Genotyping (ABI, Foster City, CA) platform was used to investigate single nucleotide polymorphisms (SNPs) across the superoxide dismutase (SOD) 1 and 2 genes to assess their association with MM risk. The study population included 329 trio (affected child and both parents) and 281 duo (affected child and one parent) families. Only cases with documented MM were studied. Seventeen SNPs across the SOD1 and SOD2 genes met the quality-control criteria to be considered for statistical analysis. Genetic association was assessed using the family-based transmission disequilibrium test in PLINK (a genome association analysis toolset).Four SNPs in the SOD1 gene (rs 202446, rs202447, rs4816405, and rs2070424) and one SNP in the SOD2 gene ( rs5746105) [corrected] appeared to be associated with MM risk in our population. After adjusting for multiple testing, these SNPs remained significant.This study provides the first genetic evidence to support association of myelomeningocele with superoxide scavenging. The rare alleles of the five specific SNPs within SOD1 and SOD2 appear to confer a protective effect on the susceptibility for MM risk in the MM population tested. Further evaluation of the roles of superoxide scavenging and neural tube development is warranted.

| S-EPMC3506000 | biostudies-literature

Acylation of Superoxide Dismutase 1 (SOD1) at K122 Governs SOD1-Mediated Inhibition of Mitochondrial Respiration.

Project description:In this study, we employed proteomics to identify mechanisms of posttranslational regulation on cell survival signaling proteins. We focused on Cu-Zn superoxide dismutase (SOD1), which protects cells from oxidative stress. We found that acylation of K122 on SOD1, while not impacting SOD1 catalytic activity, suppressed the ability of SOD1 to inhibit mitochondrial metabolism at respiratory complex I. We found that deacylase depletion increased K122 acylation on SOD1, which blocked the suppression of respiration in a K122-dependent manner. In addition, we found that acyl-mimicking mutations at K122 decreased SOD1 accumulation in mitochondria, initially hinting that SOD1 may inhibit respiration directly within the intermembrane space (IMS). However, surprisingly, we found that forcing the K122 acyl mutants into the mitochondria with an IMS-targeting tag did not recover their ability to suppress respiration. Moreover, we found that suppressing or boosting respiration levels toggled SOD1 in or out of the mitochondria, respectively. These findings place SOD1-mediated inhibition of respiration upstream of its mitochondrial localization. Lastly, deletion-rescue experiments show that a respiration-defective mutant of SOD1 is also impaired in its ability to rescue cells from toxicity caused by SOD1 deletion. Together, these data suggest a previously unknown interplay between SOD1 acylation, metabolic regulation, and SOD1-mediated cell survival.

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Cu/Zn Superoxide Dismutase (Sod1) regulates the canonical Wnt signaling pathway.

Project description:Cu/Zn Superoxide Dismutase (Sod1) catalyzes the disproportionation of cytotoxic superoxide radicals (O2•-) into oxygen (O2) and hydrogen peroxide (H2O2), a key signaling molecule. In Saccharomyces cerevisiae, we previously discovered that Sod1 participates in an H2O2-mediated redox signaling circuit that links nutrient availability to the control of energy metabolism. In response to glucose and O2, Sod1-derived H2O2 stabilizes a pair of conserved plasma membrane kinases - yeast casein kinase 1 and 2 (Yck1/2) - that signal glycolytic growth and the repression of respiration. The Yck1/2 homolog in humans, casein kinase 1-γ (CK1γ), is an integral component of the Wingless and Int-1 (Wnt) signaling pathway, which is essential for regulating cell fate and proliferation in early development and adult tissue and is dysregulated in many cancers. Herein, we establish the conservation of the SOD1/YCK1 redox signaling axis in humans by finding that SOD1 regulates CK1γ expression in human embryonic kidney 293 (HEK293) cells and is required for canonical Wnt signaling and Wnt-dependent cell proliferation.

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RNA-seq of NSC-34 cells expressing SOD1

Project description:Misfolded soluble trimeric species of superoxide dismutase 1 (SOD1) are associated with increased death in neuron-like cell models and greater disease severity in amyotrophic lateral sclerosis (ALS) patients compared to insoluble protein aggregates. The mechanism by which structurally independent SOD1 trimers cause cellular toxicity is unknown but may be a driver of disease pathology. Here, we uncovered the SOD1 trimer transcriptome. We identified key pathways using transcriptomic data from motor neuron-like cells (NSC-34s) expressing SOD1 trimers. We discovered differential gene expression in cells that express SOD1 trimers with selective enrichment of genes responsible for protein localization to membranes and a global upregulation of cellular senescence pathways. Our investigation highlights key protein factors and pathways within each system, revealing a plausible intersection of genetic and pathophysiological mechanisms in ALS through interactions involving SOD1 trimers.

2024-10-09 | GSE263048 | GEO

Conformational dynamics of superoxide dismutase (SOD1) in osmolytes: a molecular dynamics simulation study.

Project description:Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease caused by the misfolding of Cu, Zn superoxide dismutase (SOD1). Several earlier studies have shown that monomeric apo SOD1 undergoes significant local unfolding dynamics and is the predecessor for aggregation. Here, we have employed atomistic molecular dynamics (MD) simulations to study the structure and dynamics of monomeric apo and holo SOD1 in water, aqueous urea and aqueous urea-TMAO (trimethylamine oxide) solutions. Loop IV (zinc-binding loop) and loop VII (electrostatic loop) of holo SOD1 are considered as functionally important loops as they are responsible for the structural stability of holo SOD1. We found larger local unfolding of loop IV and VII of apo SOD1 as compared to holo SOD1 in water. Urea induced more unfolding in holo SOD1 than apo SOD1, whereas the stabilization of both the form of SOD1 was observed in ternary solution (i.e. water/urea/TMAO solution) but the extent of stabilization was higher in holo SOD1 than apo SOD1. The partially unfolded structures of apo SOD1 in water, urea and holo SOD1 in urea were identified by the exposure of the hydrophobic cores, which are highly dynamic and these may be the initial events of aggregation in SOD1. Our simulation studies support the formation of aggregates by means of the local unfolding of monomeric apo SOD1 as compared to holo SOD1 in water.

| S-EPMC9055598 | biostudies-literature

Superoxide Dismutase Gene (SOD1, SOD2, and SOD3) Polymorphisms and Antituberculosis Drug-induced Hepatitis.

Project description:PurposeDrug-induced liver injury (DILI) is a serious issue often leading to discontinuation of the proper regimen of antituberculosis drugs (ATD). Previous studies have suggested that antioxidant enzymes play an important role in DILI.MethodsWe explored whether polymorphisms in superoxide dismutase genes, including Cu/Zn superoxide dismutase (SOD1), manganese superoxide dismutase (SOD2) and extracellular superoxide dismutase (SOD3) are associated with ATD-induced hepatitis. Genotype distributions of four single nucleotide polymorphisms (SNPs) in three genes (rs2070424, SOD1; rs4880, SOD2; rs2536512, and rs1799895, SOD3) were compared between 84 patients with ATD-induced hepatitis and 237 patients tolerant to ATD.ResultsIntron SNP rs2070424 of SOD1 showed a significant association with ATD-induced hepatitis. The frequency of genotypes carrying minor alleles (GA or GG) was significantly higher in the case group than that of controls (P=0.019, OR=2.26, 95% CI 1.14-4.49). For the other SNPs of SOD2 and SOD3, there were no differences in genotype frequencies between ATD-induced hepatitis and ATD-tolerant controls.ConclusionsThese findings suggest that rs2070424 of SOD1 is significantly associated with ATD-induced hepatitis. This genetic variant may be a risk factor for ATD-induced hepatitis in individuals from Korea.

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Modifications of superoxide dismutase (SOD1) in human erythrocytes: a possible role in amyotrophic lateral sclerosis.

Project description:Over 100 mutations in Cu/Zn-superoxide dismutase (SOD1) result in familial amyotrophic lateral sclerosis. Dimer dissociation is the first step in SOD1 aggregation, and studies suggest nearly every amino acid residue in SOD1 is dynamically connected to the dimer interface. Post-translational modifications of SOD1 residues might be expected to have similar effects to mutations, but few modifications have been identified. Here we show, using SOD1 isolated from human erythrocytes, that human SOD1 is phosphorylated at threonine 2 and glutathionylated at cysteine 111. A second SOD1 phosphorylation was observed and mapped to either Thr-58 or Ser-59. Cysteine 111 glutathionylation promotes SOD1 monomer formation, a necessary initiating step in SOD1 aggregation, by causing a 2-fold increase in the K(d). This change in the dimer stability is expected to result in a 67% increase in monomer concentration, 315 nm rather than 212 nm at physiological SOD1 concentrations. Because protein glutathionylation is associated with redox regulation, our finding that glutathionylation promotes SOD1 monomer formation supports a model in which increased oxidative stress promotes SOD1 aggregation.

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Project description:Mutant superoxide dismutase 1 (SOD1) can be constitutively released from motor neurons and transmitted to naïve motor neurons to promote the progression of amyotrophic lateral sclerosis (ALS). However, the biological impacts of this process and the precise mechanisms of SOD1 release remain to be fully resolved. Using biochemical and fluorescent techniques, this study aimed to determine if P2X7 receptor activation could induce mutant SOD1 release from motor neurons and whether this released SOD1 could be transmitted to motor neurons or microglia to mediate effects associated with neurodegeneration in ALS. Aggregated SOD1G93A, released from murine NSC-34 motor neurons transiently transfected with SOD1G93A, could be transmitted to naïve NSC-34 cells and murine EOC13 microglia to induce endoplasmic reticulum (ER) stress and tumour necrosis factor-alpha (TNFα) release, respectively. Immunoblotting revealed NSC-34 cells expressed P2X7. Extracellular ATP induced cation dye uptake into these cells, which was blocked by the P2X7 antagonist AZ10606120, demonstrating these cells express functional P2X7. Moreover, ATP induced the rapid release of aggregated SOD1G93A from NSC-34 cells transiently transfected with SOD1G93A, a process blocked by AZ10606120 and revealing a role for P2X7 in this process. ATP-induced SOD1G93A release coincided with membrane blebbing. Finally, aggregated SOD1G93A released via P2X7 activation could also be transmitted to NSC-34 and EOC13 cells to induce ER stress and TNFα release, respectively. Collectively, these results identify a novel role for P2X7 in the prion-like propagation of SOD1 in ALS and provide a possible explanation for the therapeutic benefits of P2X7 antagonism previously observed in ALS SOD1G93A mice.

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Human superoxide dismutase 1 (hSOD1) maturation through interaction with human copper chaperone for SOD1 (hCCS).

Project description:Copper chaperone for superoxide dismutase 1 (SOD1), CCS, is the physiological partner for the complex mechanism of SOD1 maturation. We report an in vitro model for human CCS-dependent SOD1 maturation based on the study of the interactions of human SOD1 (hSOD1) with full-length WT human CCS (hCCS), as well as with hCCS mutants and various truncated constructs comprising one or two of the protein's three domains. The synergy between electrospray ionization mass spectrometry (ESI-MS) and NMR is fully exploited. This is an in vitro study of this process at the molecular level. Domain 1 of hCCS is necessary to load hSOD1 with Cu(I), requiring the heterodimeric complex formation with hSOD1 fostered by the interaction with domain 2. Domain 3 is responsible for the catalytic formation of the hSOD1 Cys-57-Cys-146 disulfide bond, which involves both hCCS Cys-244 and Cys-246 via disulfide transfer.

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