AL amyloidosis is a life-threatening disease caused by deposition of immunoglobulin light chains. While the mechanisms underlying light chains amyloidogenesis remain unclear, several studies have highlighted the role that tissue environment and structural amyloidogenicity of individual light chains have in the disease pathogenesis. AL natural deposits contain both full-length light chains and fragments encompassing the variable domain (V) as well as different length segments of the constant region (C), thus highlighting the relevance that proteolysis may have in the fibrillogenesis pathway. Here, we investigate the role of major truncated species of the disease-associated AL55 light chain that were previously identified in natural deposits. Specifically, we study structure, molecular dynamics, thermal stability, and capacity to form fibrils of a fragment containing both the V and part of the C (133-AL55), in comparison with the full-length protein and its variable domain alone, under shear stress and physiological conditions. Whereas the full-length light chain forms exclusively amorphous aggregates, both fragments generate fibrils, although, with different kinetics, aggregate structure, and interplay with the unfragmented protein. More specifically, the V-C 133-AL55 fragment entirely converts into amyloid fibrils microscopically and spectroscopically similar to their counterpart and increases the amorphous aggregation of full-length AL55. Overall, our data support the idea that light chain structure and proteolysis are both relevant for amyloidogenesis and provide a novel biocompatible model of light chain fibrillogenesis suitable for future mechanistic studies.

中文翻译：

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恒定结构域的截短通过免疫球蛋白轻链驱动淀粉样蛋白形成

AL 淀粉样变性是一种由免疫球蛋白轻链沉积引起的危及生命的疾病。虽然轻链淀粉样变性的机制尚不清楚，但一些研究强调了组织环境和单个轻链的结构淀粉样变性在疾病发病机制中的作用。 AL 天然沉积物含有全长轻链和包含可变结构域 (V) 的片段以及恒定区 (C) 的不同长度片段，从而突出了蛋白水解在纤维形成途径中可能具有的相关性。在这里，我们研究了先前在自然沉积物中发现的与疾病相关的 AL55 轻链的主要截短物种的作用。具体来说，我们研究了包含 V 和部分 C (133-AL55) 的片段的结构、分子动力学、热稳定性和形成原纤维的能力，并与单独的全长蛋白及其可变结构域进行比较。剪切应力和生理条件。尽管全长轻链仅形成无定形聚集体，但两个片段均产生原纤维，尽管具有不同的动力学、聚集体结构以及与未片段化蛋白质的相互作用。更具体地说，VC 133-AL55 片段在显微镜下和光谱上与其对应物类似地完全转化为淀粉样原纤维，并增加了全长 AL55 的无定形聚集。总的来说，我们的数据支持这样的观点，即轻链结构和蛋白水解都与淀粉样蛋白生成相关，并提供了适合未来机制研究的轻链纤维生成的新型生物相容性模型。