Endogenously Nitrated Proteins in Mouse Brain: Links to Neurodegenerative Disease
- 8 June 2006
- journal article
- research article
- Published by American Chemical Society (ACS) in Biochemistry
- Vol. 45 (26), 8009-8022
- https://doi.org/10.1021/bi060474w
Abstract
Increased abundance of nitrotyrosine modifications of proteins have been documented in multiple pathologies in a variety of tissue types and play a role in the redox regulation of normal metabolism. To identify proteins sensitive to nitrating conditions in vivo, a comprehensive proteomic data set identifying 7792 proteins from a whole mouse brain, generated by LC/LC−MS/MS analyses, was used to identify nitrated proteins. This analysis resulted in the identification of 31 unique nitrotyrosine sites within 29 different proteins. More than half of the nitrated proteins that have been identified are involved in Parkinson's disease, Alzheimer's disease, or other neurodegenerative disorders. Similarly, nitrotyrosine immunoblots of whole brain homogenates show that treatment of mice with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), an experimental model of Parkinson's disease, induces an increased level of nitration of the same protein bands observed to be nitrated in brains of untreated animals. Comparing sequences and available high-resolution structures around nitrated tyrosines with those of unmodified sites indicates a preference of nitration in vivo for surface accessible tyrosines in loops, a characteristic consistent with peroxynitrite-induced tyrosine modification. In addition, most sequences contain cysteines or methionines proximal to nitrotyrosines, contrary to suggestions that these amino acid side chains prevent tyrosine nitration. More striking is the presence of a positively charged moiety near the sites of nitration, which is not observed for non-nitrated tyrosines. Together, these observations suggest a predictive tool of functionally important sites of nitration and that cellular nitrating conditions play a role in neurodegenerative changes in the brain.Keywords
This publication has 45 references indexed in Scilit:
- A proteomic approach in the study of an animal model of Parkinson's diseaseClinica Chimica Acta; International Journal of Clinical Chemistry, 2005
- RNA association and nucleocytoplasmic shuttling by ataxin-1Journal of Cell Science, 2005
- Synapses and Sisyphus: life without parapleginJCI Insight, 2004
- Nitration inhibits fibrillation of human α‐synuclein in vitro by formation of soluble oligomersFEBS Letters, 2003
- Selective Nitration of Tyr99in Calmodulin as a Marker of Cellular Conditions of Oxidative StressChemical Research in Toxicology, 2003
- Predicting transmembrane protein topology with a hidden markov model: application to complete genomesJournal of Molecular Biology, 2001
- Sequence and structure-based prediction of eukaryotic protein phosphorylation sitesJournal of Molecular Biology, 1999
- Large modular proteins by NMRNature Structural & Molecular Biology, 1997
- DOMAIN CLOSURE IN MITOCHONDRIAL ASPARTATE-AMINOTRANSFERASEJournal of Molecular Biology, 1992
- A simple method for displaying the hydropathic character of a proteinJournal of Molecular Biology, 1982