人溶菌酶抑制系统性AA淀粉样变性患者血清淀粉样蛋白的纤颤。

IF 5.2 2区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY
Tim Moderer, Ioana Puşcalău-Gîrţu, Christian Haupt, Julian Baur, Armando Rodríguez-Alfonso, Sebastian Wiese, Christoph Q Schmidt, Miroslav Malešević, Wolf-Georg Forssmann, Ludger Ständker, Marcus Fändrich
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引用次数: 1

摘要

背景:系统性AA淀粉样变性是一种在人类和动物中普遍发生的蛋白质错误折叠疾病,由血清淀粉样蛋白a (SAA)蛋白形成淀粉样原纤维并在多个器官沉积引起。目的:鉴定阻止SAA蛋白成纤维的新药物并确定其作用方式。材料和方法:我们使用SAA蛋白形成淀粉样蛋白沉积的细胞模型来筛选从人血液滤液中纯化的肽和小蛋白库。为了阐明抑制机制,获得的抑制剂在无细胞纤维形成试验和其他生化方法中进行了表征。结果:我们鉴定出溶菌酶是SAA纤维形成的抑制剂。溶菌酶在细胞模型和无细胞纤维形成实验中均能拮抗纤维的形成。该蛋白结合SAA的解离常数为16.5±0.6µM, SAA上的结合位点由带正电的氨基酸片段构成。结论:我们的数据表明溶菌酶以伴侣样的方式起作用,并通过直接的物理相互作用阻止SAA蛋白的聚集。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Human lysozyme inhibits the fibrillation of serum amyloid a protein from systemic AA amyloidosis.

Background: Systemic AA amyloidosis is a world-wide occurring protein misfolding disease in humans and animals that arises from the formation of amyloid fibrils from serum amyloid A (SAA) protein and their deposition in multiple organs.

Objective: To identify new agents that prevent fibril formation from SAA protein and to determine their mode of action.

Materials and methods: We used a cell model for the formation of amyloid deposits from SAA protein to screen a library of peptides and small proteins, which were purified from human hemofiltrate. To clarify the inhibitory mechanism the obtained inhibitors were characterised in cell-free fibril formation assays and other biochemical methods.

Results: We identified lysozyme as an inhibitor of SAA fibril formation. Lysozyme antagonised fibril formation both in the cell model as well as in cell-free fibril formation assays. The protein binds SAA with a dissociation constant of 16.5 ± 0.6 µM, while the binding site on SAA is formed by segments of positively charged amino acids.

Conclusion: Our data imply that lysozyme acts in a chaperone-like fashion and prevents the aggregation of SAA protein through direct, physical interactions.

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来源期刊
Amyloid-Journal of Protein Folding Disorders
Amyloid-Journal of Protein Folding Disorders 生物-生化与分子生物学
CiteScore
10.60
自引率
10.90%
发文量
48
审稿时长
6-12 weeks
期刊介绍: Amyloid: the Journal of Protein Folding Disorders is dedicated to the study of all aspects of the protein groups and associated disorders that are classified as the amyloidoses as well as other disorders associated with abnormal protein folding. The journals major focus points are: etiology, pathogenesis, histopathology, chemical structure, nature of fibrillogenesis; whilst also publishing papers on the basic and chemical genetic aspects of many of these disorders. Amyloid is recognised as one of the leading publications on amyloid protein classifications and the associated disorders, as well as clinical studies on all aspects of amyloid related neurodegenerative diseases and major clinical studies on inherited amyloidosis, especially those related to transthyretin. The Journal also publishes book reviews, meeting reports, editorials, thesis abstracts, review articles and symposia in the various areas listed above.
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