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首页> 外文期刊>Biochemistry >Endogenously nitrated proteins in mouse brain: Links to neurodegenerative disease
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Endogenously nitrated proteins in mouse brain: Links to neurodegenerative disease

机译：小鼠大脑中的内源性硝化蛋白质：与神经退行性疾病的联系

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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.
机译：在各种组织类型的多种病理学中，已经证明蛋白质硝基酪氨酸修饰的丰度增加，并且在正常代谢的氧化还原调节中起作用。为了鉴定体内对硝化条件敏感的蛋白质，使用了通过LC / LC-MS / MS分析生成的从整个小鼠大脑中鉴定出7792种蛋白质的综合蛋白质组学数据来鉴定硝化的蛋白质。该分析结果鉴定出29种不同蛋白质中31个独特的硝基酪氨酸位点。已经鉴定出的硝化蛋白质中，有一半以上与帕金森氏病，阿尔茨海默氏病或​​其他神经退行性疾病有关。同样，全脑匀浆的硝基酪氨酸免疫印迹表明，用帕金森氏病的实验模型1-甲基-4-苯基-1,2,3,6-四氢吡啶（MPTP）处理小鼠，可诱导小鼠脑内硝化水平的提高。在未经治疗的动物的大脑中观察到相同的蛋白带被硝化。比较硝化酪氨酸周围的序列和可用的高分辨率结构与未修饰位点周围的序列，可以发现体内硝化优先选择环中表面可及的酪氨酸，这一特征与过氧亚硝酸盐诱导的酪氨酸修饰一致。另外，与这些氨基酸侧链阻止酪氨酸硝化的建议相反，大多数序列含有在硝基酪氨酸附近的半胱氨酸或蛋氨酸。更引人注目的是在硝化位点附近存在带正电的部分，未硝化的酪氨酸则未观察到。总之，这些观察结果提示了功能性重要硝化部位的预测工具，并且细胞硝化条件在大脑神经退行性变化中起作用。

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