Laboratory for Mechanistic Chemistry of Biomolecules, Department of Chemistry, Keio University, Yokohama, Kanagawa 223-8522, Japan.
J Biol Chem. 2012 Oct 5;287(41):34764-75. doi: 10.1074/jbc.M112.387035. Epub 2012 Aug 13.
Aggregation of protein molecules is a pathological hallmark of many neurodegenerative diseases. Abnormal modifications have often been observed in the aggregated proteins, supporting the aggregation mechanism regulated by post-translational modifications on proteins. Modifications are in general assumed to occur in soluble proteins before aggregation, but actually it remains quite obscure when proteins are modified in the course of the aggregation. Here we focus upon aggregation of huntingtin (HTT), which causes a neurodegenerative disorder, Huntington disease, and we show that oxidation of a methionine residue in HTT occurs in vitro and also in vivo. Copper ions as well as added hydrogen peroxide are found to oxidize the methionine residue, but notably, this oxidative modification occurs only in the aggregated HTT but not in the soluble state. Furthermore, the methionine oxidation creates additional interactions among HTT aggregates and alters overall morphologies of the aggregates. We thus reveal that protein aggregates can be a target of oxidative modifications and propose that such a "post-aggregation" modification is a relevant factor to regulate properties of protein aggregates.
蛋白质分子的聚集是许多神经退行性疾病的病理学特征。在聚集的蛋白质中经常观察到异常修饰，这支持了受蛋白质翻译后修饰调节的聚集机制。一般来说，修饰被认为发生在聚集前的可溶性蛋白质中，但实际上，当蛋白质在聚集过程中发生修饰时，情况仍然相当不清楚。在这里，我们关注引起神经退行性疾病亨廷顿病的亨廷顿蛋白 (HTT) 的聚集，我们表明 HTT 中的一个蛋氨酸残基在体外和体内发生氧化。铜离子和外加的过氧化氢被发现可以氧化蛋氨酸残基，但值得注意的是，这种氧化修饰仅发生在聚集的 HTT 中，而不在可溶性状态下发生。此外，蛋氨酸氧化会在 HTT 聚集体之间产生额外的相互作用，并改变聚集体的整体形态。因此，我们揭示了蛋白质聚集体可以成为氧化修饰的靶标，并提出这种“聚集后”修饰是调节蛋白质聚集体性质的一个相关因素。
