ArticleThe Journal of biological chemistry2014
Oxidation of an exposed methionine instigates the aggregation of glyceraldehyde-3-phosphate dehydrogenase.
Article in The Journal of biological chemistry, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 24 papers.
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Who cites it
24 citing papers in PubMed, 49 citations in OpenAlex.
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- Methionine Alkylation as an Approach to Quantify Methionine Oxidation Using Mass Spectrometry.Journal of the American Society for Mass Spectrometry · 2024Article
- Accurate Proteomewide Measurement of Methionine Oxidation in Aging Mouse Brains.Journal of proteome research · 2022Article
- Dual-Functional Antioxidant and Antiamyloid Cerium Oxide Nanoparticles Fabricated by Controlled Synthesis in Water-Alcohol Solutions.Biomedicines · 2022Article
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- Open Search-Based Proteomics Reveals Widespread Tryptophan Modifications Associated with Hypoxia in Lung Cancer.Oxidative medicine and cellular longevity · 2022Article
- Disruption of the Complex between GAPDH and Hsp70 Sensitizes C6 Glioblastoma Cells to Hypoxic Stress.International journal of molecular sciences · 2021Article
- The Writers, Readers, and Erasers in Redox Regulation of GAPDH.Antioxidants (Basel, Switzerland) · 2020Review
- Glyceraldehyde-3-phosphate Dehydrogenase is a Multifaceted Therapeutic Target.Pharmaceutics · 2020Review
- Cross-talk between redox signalling and protein aggregation.Biochemical Society transactions · 2020Review
- Quantitative Analysis of in Vivo Methionine Oxidation of the Human Proteome.Journal of proteome research · 2020Article
- Glutathionylation primes soluble glyceraldehyde-3-phosphate dehydrogenase for late collapse into insoluble aggregates.Proceedings of the National Academy of Sciences of the United States of America · 2019Article
- Causative Links between Protein Aggregation and Oxidative Stress: A Review.International journal of molecular sciences · 2019Review
- Oxygen and Conformation Dependent Protein Oxidation and Aggregation by Porphyrins in Hepatocytes and Light-Exposed Cells.Cellular and molecular gastroenterology and hepatology · 2019Article
- Proteomics study of silver nanoparticles on Caco-2 cells.Toxicology in vitro : an international journal published in association with BIBRA · 2018Article
- Proteome-Wide Characterization of Phosphorylation-Induced Conformational Changes in Breast Cancer.Journal of proteome research · 2018Article
- Lessons learned from protein aggregation: toward technological and biomedical applications.Biophysical reviews · 2017Review
- Structure-function analyses of a pertussis-like toxin from pathogenicThe Journal of biological chemistry · 2017Article
Corrections and comments
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Authors and funding
10 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) is a ubiquitous and abundant protein that participates in cellular energy production. GAPDH normally exists in a soluble form; however, following necrosis, GAPDH and numerous other intracellular proteins convert into an insoluble disulfide-cross-linked state via the process of "nucleocytoplasmic coagulation." Here, free radical-induced aggregation of GAPDH was studied as an in vitro model of nucleocytoplasmic coagulation. Despite the fact that disulfide cross-linking is a prominent feature of GAPDH aggregation, our data show that it is not a primary rate-determining step. To identify the true instigating event of GAPDH misfolding, we mapped the post-translational modifications that arise during its aggregation. Solvent accessibility and energy calculations of the mapped modifications within the context of the high resolution native GAPDH structure suggested that oxidation of methionine 46 may instigate aggregation. We confirmed this by mutating methionine 46 to leucine, which rendered GAPDH highly resistant to free radical-induced aggregation. Molecular dynamics simulations suggest that oxidation of methionine 46 triggers a local increase in the conformational plasticity of GAPDH that likely promotes further oxidation and eventual aggregation. Hence, methionine 46 represents a "linchpin" whereby its oxidation is a primary event permissive for the subsequent misfolding, aggregation, and disulfide cross-linking of GAPDH. A critical role for linchpin residues in nucleocytoplasmic coagulation and other forms of free radical-induced protein misfolding should now be investigated. Furthermore, because disulfide-cross-linked aggregates of GAPDH arise in many disorders and because methionine 46 is irrelevant to native GAPDH function, mutation of methionine 46 in models of disease should allow the unequivocal assessment of whether GAPDH aggregation influences disease progression.
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