Neuroscience 2002 Abstract
| Presentation Number: | 318.1 |
|---|---|
| Abstract Title: | Oxidative modification on GAPDH; Its mechanisms for cytotoxic actions. |
| Authors: |
Sawa, A.*1
; Hara, M. R.1
; Snyder , S. H.1
1Psychiatry and Neuroscience, Johns Hopkins University, Baltimore, MD |
| Primary Theme and Topics |
Neurological and Psychiatric Conditions - Neurodegenerative Disorders -- Other |
| Secondary Theme and Topics | Neurological and Psychiatric Conditions<br />- Aging<br />-- Molecular studies |
| Session: |
318. Neurodegenerative disorders: other--mechanisms of neural degeneration Slide |
| Presentation Time: | Monday, November 4, 2002 1:00 PM-1:15 PM |
| Location: | Room 208C |
| Keywords: | oxidative stress, neurodegeneration, aging, nitric oxide |
Our group, as well as many others, has reported that a classic glycolytic enzyme, glyceraldehyde-3-phosphate dehydrogenase (GAPDH) is a multiple function protein. We have reported that oxidized GAPDH may play a role in cytotoxicity associated with its translocation to the nucleus. We have also found in vivo ADP-ribosylated GAPDH in the nucleus upon oxidative stress, probably following an initial S-nitrosylation (Hara et al SFN 2002). Here we report roles of two cysteine residues, cysteine-150 and -154 in oxidative modification of GAPDH. These two cysteine residues are well conserved among many species. To analyze their function, we have produced three kinds of GAPDH mutants, GAPDH-C150S, GAPDH-C154S, and GAPDH-C150S/C154S (double mutant) in which each cysteine residue is substituted by serine. GAPDH was ADP-ribosylated in vitro by the mixture with 32P-labeled NAD under oxidative stress. We found no ADP-ribosylation in GAPDH-C150S, which fit with the current consensus that ADP-ribosylation occurs at cysteine-150. In contrast, we found a paradoxically upregulated S-nitrosylation in GAPDH-C150S, but, no S-nitrosylation in GAPDH-C154S. These results may be interpreted as an initial S-nitrosylation at cysteine-154 and its induction of ADP-ribosylation at cysteine-150. Consistent with this hypothesis, replacement of cysteine-154 to serine abolished ADP-ribosylation of GAPDH. In other lines of evidence, we found that a cytosolic interactor of GAPDH, associated molecule of GAPDH-1 (AMG-1) modulated the initial steps of the oxidative modification of GAPDH. We are examining roles of cysteine-150 and -154 of GAPDH in its cytotoxic actions.
Supported by NIH, HDSA, Stanley, S-R foundation
Sample Citation:
[Authors]. [Abstract Title]. Program No. XXX.XX. 2002 Neuroscience Meeting Planner. Orlando, FL: Society for Neuroscience, 2002. Online.
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