小分子
体内
淀粉样蛋白(真菌学)
周质间隙
大肠杆菌
融合蛋白
计算生物学
蛋白质聚集
化学
生物化学
体外
生物
细胞生物学
基因
遗传学
重组DNA
无机化学
作者
Janet C. Saunders,Lydia M. Young,Rachel A. Mahood,Matthew P. Jackson,Charlotte Revill,Richard Foster,D. A. Smith,Alison E. Ashcroft,David J. Brockwell,Sheena E. Radford
标识
DOI:10.1038/nchembio.1988
摘要
Protein aggregation underlies an array of human diseases, yet only one small-molecule therapeutic targeting this process has been successfully developed to date. Here, we introduce an in vivo system, based on a β-lactamase tripartite fusion construct, that is capable of identifying aggregation-prone sequences in the periplasm of Escherichia coli and inhibitors that prevent their aberrant self-assembly. We demonstrate the power of the system using a range of proteins, from small unstructured peptides (islet amyloid polypeptide and amyloid β) to larger, folded immunoglobulin domains. Configured in a 48-well format, the split β-lactamase sensor readily differentiates between aggregation-prone and soluble sequences. Performing the assay in the presence of 109 compounds enabled a rank ordering of inhibition and revealed a new inhibitor of islet amyloid polypeptide aggregation. This platform can be applied to both amyloidogenic and other aggregation-prone systems, independent of sequence or size, and can identify small molecules or other factors able to ameliorate or inhibit protein aggregation.
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