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生物流体中的结构特异性淀粉样沉淀
作者:小柯机器人 发布时间:2022/7/10 12:46:18

英国剑桥大学Klenerman, D.团队报道了生物流体中的结构特异性淀粉样沉淀。相关研究成果发表在2022年7月7日出版的国际知名学术期刊《自然—化学》。

在神经退行性疾病中,体内形成的可溶性有毒蛋白质聚集体的组成目前尚不清楚,因为它们在人体生物流体中的浓度极低,并且具有高度的异质性。

该文中,研究人员报告了一种以无偏方式捕获人类生物流体中含淀粉样蛋白聚集体的方法,我们称之为淀粉样蛋白沉淀。研究人员使用一种结构特异性化学二聚体,一种具有两个捕获基团的Y形仿生小分子,用于淀粉样蛋白沉淀以增加亲和力。该淀粉样沉淀捕获分子(CAP-1)由匹兹堡化合物B(二聚体)的衍生物组成,以靶向淀粉样蛋白的交叉β-片和用于表面固定的生物素部分。

通通过将CAP-1偶联到磁珠上,研究人员可以靶向人类脑脊液中存在的所有蛋白质聚集体的淀粉样结构,并分离它们进行分析,然后使用单分子荧光成像和质谱对其进行表征。淀粉样沉淀能够无偏地测定神经退行性疾病中形成的体内聚集体的分子组成和结构特征。

附:英文原文

Title: Structure-specific amyloid precipitation in biofluids

Author: Rodrigues, M., Bhattacharjee, P., Brinkmalm, A., Do, D. T., Pearson, C. M., De, S., Ponjavic, A., Varela, J. A., Kulenkampff, K., Baudrexel, I., Emin, D., Ruggeri, F. S., Lee, J. E., Carr, A. R., Knowles, T. P. J., Zetterberg, H., Snaddon, T. N., Gandhi, S., Lee, S. F., Klenerman, D.

Issue&Volume: 2022-07-07

Abstract: The composition of soluble toxic protein aggregates formed in vivo is currently unknown in neurodegenerative diseases, due to their ultra-low concentration in human biofluids and their high degree of heterogeneity. Here we report a method to capture amyloid-containing aggregates in human biofluids in an unbiased way, a process we name amyloid precipitation. We use a structure-specific chemical dimer, a Y-shaped, bio-inspired small molecule with two capture groups, for amyloid precipitation to increase affinity. Our capture molecule for amyloid precipitation (CAP-1) consists of a derivative of Pittsburgh Compound B (dimer) to target the cross β-sheets of amyloids and a biotin moiety for surface immobilization. By coupling CAP-1 to magnetic beads, we demonstrate that we can target the amyloid structure of all protein aggregates present in human cerebrospinal fluid, isolate them for analysis and then characterize them using single-molecule fluorescence imaging and mass spectrometry. Amyloid precipitation enables unbiased determination of the molecular composition and structural features of the in vivo aggregates formed in neurodegenerative diseases.

DOI: 10.1038/s41557-022-00976-3

Source: https://www.nature.com/articles/s41557-022-00976-3

期刊信息

Nature Chemistry:《自然—化学》,创刊于2009年。隶属于施普林格·自然出版集团,最新IF:21.687
官方网址:https://www.nature.com/nchem/
投稿链接:https://mts-nchem.nature.com/cgi-bin/main.plex