Zottig Ximena, Laporte Wolwertz Mathieu, Golizeh Makan, Ohlund Leanne, Sleno Lekha, Bourgault Steve
Department of Chemistry, Pharmaqam, University of Québec in Montreal, Montreal, QC H3C 3P8, Canada; Quebec Network for Research on Protein Function, Engineering and Applications, PROTEO, Canada.
Department of Chemistry, Pharmaqam, University of Québec in Montreal, Montreal, QC H3C 3P8, Canada.
Biophys Chem. 2016 Dec;219:59-68. doi: 10.1016/j.bpc.2016.10.001. Epub 2016 Oct 11.
Light chain amyloidosis (AL) originates from the deposition of immunoglobulin light chains (LCs) as amyloid fibrils in the extracellular space of vital organs. Although non-enzymatic post-translational modifications (PTMs) have been shown to contribute to protein misfolding diseases, little is known about their contributions to LC amyloidogenicity. In this study, we investigated the effects of three oxidative PTMs, carbonylation by hydroxynonenal (HNE), oxidation and nitration, on the structure, thermodynamic stability and self-assembly propensity of a LC variable domain from the λ6 germline, Wil. We initially identified the specific residues that are susceptible to oxidative chemical modifications. HNE-conjugation at specific His residues and nitration of Tyr side chains modulated the conformational conversion driving Wil self-assembly and fibrillar aggregates formation. This study reinforces the notion that not only the thermodynamic stability, but also the chemical and structural properties, should be considered when evaluating the amyloidogenic potential of a LC.
轻链淀粉样变性（AL）源于免疫球蛋白轻链（LCs）以淀粉样纤维的形式沉积在重要器官的细胞外空间。尽管非酶促翻译后修饰（PTMs）已被证明与蛋白质错误折叠疾病有关，但对于它们对LC淀粉样变性的作用却知之甚少。在本研究中，我们研究了三种氧化PTMs，即羟基壬烯醛（HNE）介导的羰基化、氧化和硝化，对来自λ6种系Wil的LC可变结构域的结构、热力学稳定性和自组装倾向的影响。我们首先确定了易受氧化化学修饰影响的特定残基。特定组氨酸残基处的HNE共轭和酪氨酸侧链的硝化调节了驱动Wil自组装和纤维状聚集体形成的构象转变。这项研究强化了这样一种观念，即在评估LC淀粉样变性潜力时，不仅应考虑热力学稳定性，还应考虑化学和结构性质。
