Modulation of amyloid assembly by glycosaminoglycans: from mechanism to biological significance.

Noé Quittot, M. Sebastiao, S. Bourgault
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引用次数: 29

Abstract

Glycosaminoglycans (GAGs) are long and unbranched polysaccharides that are abundant in the extracellular matrix and basement membrane of multicellular organisms. These linear polyanionic macromolecules are involved in many physiological functions from cell adhesion to cellular signaling. Interestingly, amyloid fibrils extracted from patients afflicted with protein misfolding diseases are virtually always associated with GAGs. Amyloid fibrils are highly organized nanostructures that have been historically associated with pathological states, such as Alzheimer's disease and systemic amyloidoses. However, recent studies have identified functional amyloids that accomplish crucial physiological roles in almost all living organisms, from bacteria to insects and mammals. Over the last 2 decades, numerous reports have revealed that sulfated GAGs accelerate and (or) promote the self-assembly of a large diversity of proteins, both inherently amyloidogenic and non-aggregation prone. Despite the fact that many studies have investigated the molecular mechanism(s) by which GAGs induce amyloid assembly, the mechanistic elucidation of GAG-mediated amyloidogenesis still remains the subject of active research. In this review, we expose the contribution of GAGs in amyloid assembly, and we discuss the pathophysiological and functional significance of GAG-mediated fibrillization. Finally, we propose mechanistic models of the unique and potent ability of sulfated GAGs to hasten amyloid fibril formation.
糖胺聚糖对淀粉样蛋白组装的调节:从机制到生物学意义。
糖胺聚糖(Glycosaminoglycans, GAGs)是一种长而无支链的多糖,广泛存在于多细胞生物的细胞外基质和基底膜中。这些线性多阴离子大分子参与许多生理功能,从细胞粘附到细胞信号传导。有趣的是,从患有蛋白质错误折叠疾病的患者身上提取的淀粉样蛋白原纤维实际上总是与gag相关。淀粉样原纤维是高度组织化的纳米结构,历史上与病理状态有关,如阿尔茨海默病和全身性淀粉样变性。然而,最近的研究已经发现,功能性淀粉样蛋白在几乎所有生物体中都发挥着至关重要的生理作用,从细菌到昆虫和哺乳动物。在过去的20年里,大量的报道表明,硫酸盐酸化的gag加速和(或)促进了大量蛋白质的自组装,这些蛋白质既有固有的淀粉样蛋白,也有不聚集的倾向。尽管许多研究已经研究了GAGs诱导淀粉样蛋白组装的分子机制,但对GAGs介导的淀粉样蛋白形成的机制阐明仍然是一个活跃的研究课题。在这篇综述中,我们揭示了gag在淀粉样蛋白组装中的作用,并讨论了gag介导的纤维化的病理生理和功能意义。最后,我们提出了独特而有效的硫酸化gag加速淀粉样蛋白纤维形成的机制模型。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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