Endogenously Nitrated Proteins in Mouse Brain: Links to Neurodegenerative Disease

详细信息    查看全文

• 作者：Colette A. Sacksteder ; Wei-Jun Qian ; Tatyana V. Knyushko ; Haixing Wang ; Mark H. Chin ; Goran Lacan ; William P. Melega ; David G. Camp ; II ; Richard D. Smith ; Desmond J. Smith ; Thomas C. Squier ; and Dian
• 刊名：Biochemistry
• 出版年：2006
• 出版时间：July 4, 2006
• 年：2006
• 卷：45
• 期：26
• 页码：8009 - 8022
• 全文大小：362K
• 年卷期：v.45,no.26(July 4, 2006)
• ISSN：1520-4995

文摘

Increased abundance of nitrotyrosine modifications of proteins have been documented in multiplepathologies in a variety of tissue types and play a role in the redox regulation of normal metabolism. Toidentify proteins sensitive to nitrating conditions in vivo, a comprehensive proteomic data set identifying7792 proteins from a whole mouse brain, generated by LC/LC-MS/MS analyses, was used to identifynitrated proteins. This analysis resulted in the identification of 31 unique nitrotyrosine sites within 29different proteins. More than half of the nitrated proteins that have been identified are involved inParkinson's disease, Alzheimer's disease, or other neurodegenerative disorders. Similarly, nitrotyrosineimmunoblots 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 ofnitration of the same protein bands observed to be nitrated in brains of untreated animals. Comparingsequences and available high-resolution structures around nitrated tyrosines with those of unmodifiedsites indicates a preference of nitration in vivo for surface accessible tyrosines in loops, a characteristicconsistent with peroxynitrite-induced tyrosine modification. In addition, most sequences contain cysteinesor methionines proximal to nitrotyrosines, contrary to suggestions that these amino acid side chains preventtyrosine 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 offunctionally important sites of nitration and that cellular nitrating conditions play a role in neurodegenerativechanges in the brain.