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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Microtubule dysfunction by posttranslational nitrotyrosination of a#alpha#-tubulin: A nitric oxide-dependent mechanism of cellular injure
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Microtubule dysfunction by posttranslational nitrotyrosination of a#alpha#-tubulin: A nitric oxide-dependent mechanism of cellular injure

机译：通过翻译后硝基酪氨酸a＃alpha＃-微管蛋白的微管功能障碍：一氧化氮依赖的细胞损伤机制。

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摘要

NO_2Tyr (3-Nitrotyrosine) is a modified amino acid that is formed by nitric oxide-derived specics and has been implicated in the pathology of diverse human dis- eases. Nitration of active-site tyrosine residues is known to compromise protein structure and function. Although free NO_2Tyr is produced in abundant concentrations under patho- logical conditions, its capacity to alter protein structure and function at the translational or posttranslational level is unknown. Here, we report that free NO_2Tyr is transported into mammalian cells and selectively incorporated into the extreme carboxyl terminus of #alpha#-tubulin via a posttransla- tional mechanism catalyzed by the enzyme tubulin-tyrosine ligase. In contrast to the enzymatically regulated carboxyl- terminal tyrosination/detyrosination cycle of #alpha#-tubulin, in- corporation of NO_2Tyr shows apparent irreversibility. Nitro- tyrosination of #alpha#-tubulin induces alterations in cell morphol- ogy, changes in microtubule organization, loss of epithelial- barrier function, and intracellular redistribution of the motor protein cytoplasmic dynein. These observations imply that posttranslational nitrotyrosination of #alpha#-tubulin invokes con- formational changes, eithcr directly or via allosteric interac- tions, in the surface-exposed carboxyl terminus of #alpha#-tubulin that compromises the function of this critical domain in regulating microtubule organization and binding of motor- and microtubule-associated proteins. Collectively, these ob- servations illustrate a mechanism whereby free NO_2Tyr can impact deleteriousl
机译：NO_2Tyr（3-硝基酪氨酸）是一种修饰的氨基酸，由一氧化氮衍生的物种形成，并已涉及多种人类疾病的病理学。已知活性位点酪氨酸残基的硝化会损害蛋白质的结构和功能。尽管游离NO_2Tyr在病理条件下浓度很高，但在翻译或翻译后水平改变蛋白质结构和功能的能力尚不清楚。在这里，我们报道游离NO_2Tyr被转运到哺乳动物细胞中，并通过微管蛋白-酪氨酸连接酶催化的后翻译机制选择性地掺入＃alpha＃-微管蛋白的极端羧基末端。与＃alpha＃-微管蛋白的酶促调节羧基末端酪氨酸/去酪氨酸循环相反，NO_2Tyr的结合表现出明显的不可逆性。 ＃alpha＃-微管蛋白的硝基酪氨酸诱导细胞形态改变，微管组织改变，上皮屏障功能丧失和运动蛋白胞质动力蛋白的细胞内重新分布。这些观察结果暗示＃alpha＃-微管蛋白的翻译后硝基酪氨酸化直接或通过变构相互作用在＃alpha＃-微管蛋白表面暴露的羧基末端引起构象变化，从而破坏了该关键域在调节中的功能。微管的组织以及运动和微管相关蛋白的结合。总的来说，这些观察结果说明了游离NO_2Tyr可以影响有害生物的机制。

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