School of Chemistry and Chemical Engineering, Huazhong University of Science and Technology, Wuhan, 430074, People's Republic of China.
J Biol Inorg Chem. 2012 Oct;17(7):1083-91. doi: 10.1007/s00775-012-0922-z. Epub 2012 Jul 21.
Protein tyrosine nitration is a post-translational modification associated with numerous pathological conditions. The biological consequences of this modification strongly depend on the site selectivity. Unfortunately, to date there is still no reliable model for predicting the selectivity of protein tyrosine nitration. Previously, we found that amyloid beta (Aβ) changed the selectivity of enolase tyrosine nitration upon binding to heme. It seemed that there was a link between the hydrophilicity of Aβ and the site-specific tyrosine nitration. We further investigated the role of the hydrophilicity of the molecules that bind to heme in the selectivity of protein tyrosine nitration. We found that Aβ(1-16), Aβ(1-20), and Aβ(1-40), upon binding to heme and interacting with glyceraldehyde-3-phosphate dehydrogenase (GAPDH) in a site-specific manner, differently modulated the site selectivity of heme-catalyzed GAPDH tyrosine nitration. The modulation is associated with the hydrophilicity of the Aβ peptides, which changed the surrounding environment of the heme. At the same time, the Aβ-heme complexes were found to be more effective at inactivating GAPDH than heme alone, and the selective tyrosine nitration that was catalyzed by Aβ-heme played an important role. These findings suggest an alternative mechanism for the selectivity of protein tyrosine nitration, which may lead to a better understanding of the factors that influence protein tyrosine nitration selectivity and the important roles of Aβ and heme in the pathogenesis of Alzheimer's disease, where Aβ accumulation and Aβ-dependent protein nitration play central roles.
蛋白质酪氨酸硝化是一种与许多病理状况相关的翻译后修饰。这种修饰的生物学后果强烈依赖于位点选择性。不幸的是，迄今为止，仍然没有可靠的模型可以预测蛋白质酪氨酸硝化的选择性。之前，我们发现淀粉样β（Aβ）在与血红素结合后改变了烯醇酶酪氨酸硝化的选择性。似乎 Aβ 的亲水性与特定酪氨酸硝化之间存在联系。我们进一步研究了与血红素结合的分子的亲水性在蛋白质酪氨酸硝化选择性中的作用。我们发现 Aβ（1-16）、Aβ（1-20）和 Aβ（1-40）与血红素结合并以特定方式与甘油醛-3-磷酸脱氢酶（GAPDH）相互作用，不同程度地调节了血红素催化 GAPDH 酪氨酸硝化的位点选择性。这种调节与 Aβ 肽的亲水性有关，亲水性改变了血红素的周围环境。同时，发现 Aβ-血红素复合物比血红素本身更有效地使 GAPDH 失活，并且 Aβ-血红素催化的选择性酪氨酸硝化起着重要作用。这些发现为蛋白质酪氨酸硝化的选择性提供了一种替代机制，可能有助于更好地理解影响蛋白质酪氨酸硝化选择性的因素，以及 Aβ 和血红素在阿尔茨海默病发病机制中的重要作用，其中 Aβ 积累和 Aβ 依赖性蛋白硝化起着核心作用。
