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Inherent Biophysical Properties Modulate the Toxicity of Soluble Amyloidogenic Light Chains.
Journal of Molecular Biology ( IF 4.7 ) Pub Date : 2019-12-24 , DOI: 10.1016/j.jmb.2019.12.015
Martina Maritan 1 , Margherita Romeo 2 , Luca Oberti 1 , Pietro Sormanni 3 , Masayoshi Tasaki 4 , Rosaria Russo 5 , Arianna Ambrosetti 1 , Paolo Motta 5 , Paola Rognoni 6 , Giulia Mazzini 6 , Alberto Barbiroli 7 , Giovanni Palladini 6 , Michele Vendruscolo 3 , Luisa Diomede 2 , Martino Bolognesi 8 , Giampaolo Merlini 6 , Francesca Lavatelli 6 , Stefano Ricagno 1
Affiliation  

In light chain amyloidosis (AL), fibrillar deposition of monoclonal immunoglobulin light chains (LCs) in vital organs, such as heart, is associated with their severe dysfunction. In addition to the cellular damage caused by fibril deposition, direct toxicity of soluble prefibrillar amyloidogenic proteins has been reported, in particular, for cardiotoxicity. However, the molecular bases of proteotoxicity by soluble LCs have not been clarified. Here, to address this issue, we rationally engineered the amino acid sequence of the highly cardiotoxic LC H6 by introducing three residue mutations, designed to reduce the dynamics of its native state. The resulting mutant (mH6) is less toxic than its parent H6 to human cardiac fibroblasts and C. elegans. The high sequence and structural similarity, together with the different toxicity, make H6 and its non-toxic designed variant mH6 a test case to shed light on the molecular properties underlying soluble toxicity. Our comparative structural and biochemical study of H6 and mH6 shows closely matching crystal structures, whereas spectroscopic data and limited proteolysis indicate that H6 displays poorly cooperative fold, higher flexibility, and kinetic instability, and a higher dynamic state in its native fold. Taken together, the results of this study show a strong correlation between the overall conformational properties of the native fold and the proteotoxicity of cardiotropic LCs.

中文翻译:

固有的生物物理特性可调节可溶性淀粉样蛋白轻链的毒性。

在轻链淀粉样变性(AL)中,单克隆免疫球蛋白轻链(LC)在重要器官(例如心脏)中的纤维状沉积与其严重的功能障碍有关。除了由原纤维沉积引起的细胞损伤外,已经报道了可溶性原纤维前淀粉样蛋白的直接毒性,特别是对于心脏毒性。但是,尚不清楚由可溶性LC引起的蛋白毒性的分子基础。在这里,为了解决这个问题,我们通过引入三个残基突变来合理设计高度心脏毒性LC H6的氨基酸序列,以减少其天然状态的动态。所得突变体(mH6)对人类心脏成纤维细胞和秀丽隐杆线虫的毒性小于其亲本H6。高度的序列和结构相似性,以及不同的毒性,使H6及其无毒设计的变体mH6成为测试案例,以阐明可溶毒性背后的分子特性。我们对H6和mH6的比较结构和生化研究显示出紧密匹配的晶体结构,而光谱数据和有限的蛋白水解作用表明H6表现出较差的协同折叠,较高的柔性和动力学不稳定,以及其天然折叠中较高的动态状态。两者合计,这项研究的结果表明天然褶皱的整体构象特性与向心型LCs的蛋白毒性之间有很强的相关性。而光谱数据和有限的蛋白水解作用表明H6表现出较差的协同折叠,更高的柔韧性和动力学不稳定,以及天然折叠中更高的动态状态。两者合计,这项研究的结果表明天然褶皱的整体构象特性与向心型LCs的蛋白毒性之间有很强的相关性。而光谱数据和有限的蛋白水解作用表明H6表现出较差的协同折叠,较高的柔性和动力学不稳定,以及天然折叠中较高的动态状态。两者合计,这项研究的结果表明天然褶皱的整体构象特性与向心型LCs的蛋白毒性之间有很强的相关性。
更新日期:2019-12-25
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