Binding of alpha-synuclein to partially oxidized glyceraldehyde-3-phosphate dehydrogenase induces subsequent inactivation of the enzyme.
According to literature data, the glycolytic enzyme glyceraldehyde-3-phosphate dehydrogenase (GAPDH) co-localizes with alpha-synuclein in Lewy bodies in Parkinson's disease, which suggests the involvement of this protein in the development of synucleinopathies. The goal of the present work was to investigate the direct interaction between alpha-synuclein and GAPDH and to evaluate possible influence of this interaction on the catalytic properties of GAPDH. Molecular dynamic simulations predicted the binding of alpha-synuclein to the positively charged groove comprising NAD+-binding pocket of GAPDH. The formation of the complex between alpha-synuclein and GAPDH in vitro was confirmed by different experimental approaches. The binding of alpha-synuclein to GAPDH with partially oxidized active site cysteines resulted in the subsequent inactivation of the enzyme, decreased its thermostability and increased its propensity for aggregation. At the same time, the formation of the complex between GAPDH and monomeric alpha-synuclein prevented amyloid transformation of alpha-synuclein. This work presents the first evidence for the fact that the initial oxidation of GAPDH induces the binding of alpha-synuclein to the enzyme, leading to further inactivation of GAPDH and, as a consequence, inhibition of glycolysis. The described mechanism may contribute to the metabolic disorders that are characteristic for synucleinopathies.
['Barinova|Kseniya|K|', 'Khomyakova|Evgeniya|E|', 'Semenyuk|Pavel|P|', 'Schmalhausen|Elena|E|', 'Muronetz|Vladimir|V|']
D000682:Amyloid D002384:Catalysis D020134:Catalytic Domain D003545:Cysteine D004795:Enzyme Stability D004797:Enzyme-Linked Immunosorbent Assay D005987:Glyceraldehyde-3-Phosphate Dehydrogenases D006019:Glycolysis D006801:Humans D047468:Immunoprecipitation D056004:Molecular Dynamics Simulation D010084:Oxidation-Reduction D011485:Protein Binding D012542:Scattering, Radiation D014461:Ultracentrifugation D051844:alpha-Synuclein
alpha-synuclein oxidation glyceraldehyde-3-phosphate dehydrogenase Parkinson's disease synucleinopathies glycolysis