二聚体
免疫球蛋白轻链
化学
淀粉样蛋白(真菌学)
硫黄素
蛋白质聚集
淀粉样变性
生物物理学
单体
生殖系
突变体
淀粉样变性
蛋白质结构
抗体
生物化学
生物
遗传学
基因
病理
有机化学
无机化学
医学
阿尔茨海默病
聚合物
疾病
作者
Pinaki Misra,Luis M. Blancas‐Mejía,Marina Ramı́rez-Alvarado
出处
期刊:Biochemistry
[American Chemical Society]
日期:2019-06-25
卷期号:58 (29): 3155-3168
被引量:33
标识
DOI:10.1021/acs.biochem.9b00311
摘要
Little is known about the mechanism of amyloid assembly in immunoglobulin light chain (AL) amyloidosis, in contrast to other amyloid diseases. Early events in the aggregation pathway are especially important, as these soluble species could be cytotoxic intermediates playing a critical role in the initiation of the amyloid assembly. In this work, we discuss the mechanism of the early events in in vitro fibril formation of immunoglobulin light chain AL-09 and AL-12 (involved in cardiac amyloidosis) and its germline (control) protein κI O18/O8. Previous work from our laboratory showed that AL-12 adopts a canonical dimer conformation (like the germline protein), whereas AL-09 presents an altered dimer interface as a result of somatic mutations. Both AL-12 and AL-09 aggregate with similar rates and significantly faster than the germline protein. AL-09 is the only protein in this study that forms stable oligomeric intermediates during the early stages of the aggregation reaction with some structural rearrangements that increase the thioflavin T fluorescence but maintain the same number of monomers in solution. The presence of the restorative mutation AL-09 H87Y changes the kinetics and the aggregation pathway compared to AL-09. The single restorative mutation AL-12 R65S slightly delayed the overall rate of aggregation as compared to AL-12. Collectively, our study provides a comprehensive analysis of species formed during amyloid nucleation in AL amyloidosis, shows a strong dependence between the altered dimer conformation and the formation of stable oligomeric intermediates, and sheds light on the structural features of amyloidogenic intermediates associated with cellular toxicity.
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