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Mechanism of GAPDH Redox Signaling by H 2 O 2 Activation of a Two-Cysteine Switch.
- Source :
-
International journal of molecular sciences [Int J Mol Sci] 2022 Apr 21; Vol. 23 (9). Date of Electronic Publication: 2022 Apr 21. - Publication Year :
- 2022
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Abstract
- Oxidation of glyceraldehyde-3-phosphate dehydrogenase (GAPDH) by reactive oxygen species such as H <subscript>2</subscript> O <subscript>2</subscript> activate pleiotropic signaling pathways is associated with pathophysiological cell fate decisions. Oxidized GAPDH binds chaperone proteins with translocation of the complex to the nucleus and mitochondria initiating autophagy and cellular apoptosis. In this study, we establish the mechanism by which H <subscript>2</subscript> O <subscript>2</subscript> -oxidized GAPDH subunits undergo a subunit conformational rearrangement. H <subscript>2</subscript> O <subscript>2</subscript> oxidizes both the catalytic cysteine and a vicinal cysteine (four residues downstream) to their respective sulfenic acids. A 'two-cysteine switch' is activated, whereby the sulfenic acids irreversibly condense to an intrachain thiosulfinic ester resulting in a major metastable subunit conformational rearrangement. All four subunits of the homotetramer are uniformly and independently oxidized by H <subscript>2</subscript> O <subscript>2</subscript> , and the oxidized homotetramer is stabilized at low temperatures. Over time, subunits unfold forming disulfide-linked aggregates with the catalytic cysteine oxidized to a sulfinic acid, resulting from thiosulfinic ester hydrolysis via the highly reactive thiosulfonic ester intermediate. Molecular Dynamic Simulations provide additional mechanistic insights linking GAPDH subunit oxidation with generating a putative signaling conformer. The low-temperature stability of the H <subscript>2</subscript> O <subscript>2</subscript> -oxidized subunit conformer provides an operable framework to study mechanisms associated with gain-of-function activities of oxidized GAPDH to identify novel targets for the treatment of neurodegenerative diseases.
Details
- Language :
- English
- ISSN :
- 1422-0067
- Volume :
- 23
- Issue :
- 9
- Database :
- MEDLINE
- Journal :
- International journal of molecular sciences
- Publication Type :
- Academic Journal
- Accession number :
- 35562998
- Full Text :
- https://doi.org/10.3390/ijms23094604