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首页> 外文期刊>Journal of Molecular Biology >Protein N-homocysteinylation induces the formation of toxic amyloid-like protofibrils.
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Protein N-homocysteinylation induces the formation of toxic amyloid-like protofibrils.

机译：蛋白N-同型半胱氨酸化诱导毒性淀粉样样原纤维的形成。

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摘要

Previous works reported that a mild increase in homocysteine level is a risk factor for cardiovascular and neurodegenerative diseases in humans. Homocysteine thiolactone is a cyclic thioester, most of which is produced by an error-editing function of methionyl-tRNA synthetase, causing in vivo post-translational protein modifications by reacting with the epsilon-amino group of lysine residues. In cells, the rate of homocysteine thiolactone synthesis is strictly dependent on the levels of the precursor metabolite, homocysteine. In this work, using bovine serum albumin as a model, we investigated the impact of N-homocysteinylation on protein conformation as well as its cellular actions. Previous works demonstrated that protein N-homocysteinylation causes enzyme inactivation, protein aggregation, and precipitation. In addition, in the last few years, several pieces of evidence have indicated that protein unfolding and aggregation are crucial events leading to the formation of amyloid fibrils associated with a wide range of human pathologies. For the first time, our results reveal how the low level of protein N-homocysteinylation can induce mild conformational changes leading to the formation of native-like aggregates evolving over time, producing amyloid-like structures. Taking into account the fact that in humans about 70% of circulating homocysteine is N-linked to blood proteins such as serum albumin and hemoglobin, the results reported in this article could have pathophysiological relevance and could contribute to clarify the mechanisms underlying some pathological consequences described in patients affected by hyperhomocysteinemia.
机译：先前的研究报道，同型半胱氨酸水平的轻微升高是人类心血管和神经退行性疾病的危险因素。同型半胱氨酸硫内酯是一种环状硫酯，其大部分是由甲硫酰基-tRNA合成酶的错误编辑功能产生的，通过与赖氨酸残基的ε-氨基反应，在体内引起翻译后蛋白质修饰。在细胞中，高半胱氨酸硫代内酯的合成速率严格取决于前体代谢产物高半胱氨酸的水平。在这项工作中，我们以牛血清白蛋白为模型，研究了N-高半胱氨酸化对蛋白质构象及其细胞作用的影响。先前的工作证明蛋白质N-高半胱氨酸化会导致酶失活，蛋白质聚集和沉淀。另外，在最近几年中，几项证据表明蛋白质的解开和聚集是导致与人类广泛病理相关的淀粉样蛋白原纤维形成的关键事件。我们的结果首次揭示了低水平的蛋白质N-同型半胱氨酸化作用如何诱导温和的构象变化，从而导致形成类似天然的聚集体，并随着时间的流逝而产生淀粉样结构。考虑到以下事实：在人类中，约70％的循环同型半胱氨酸与血液蛋白（如血清白蛋白和血红蛋白）N连接，因此本文报道的结果可能与病理生理相关，并且有助于阐明所描述的某些病理后果的机制在高同型半胱氨酸血症患者中。

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