期刊
NATURE CHEMICAL BIOLOGY
卷 12, 期 2, 页码 94-+出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/NCHEMBIO.1988
关键词
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资金
- Innovate UK [131841]
- Biotechnology and Biological Sciences Research Council (BBSRC) [BB/M01259X/1]
- European Research Council (ERC) under the European Union's Seventh Framework Programme (FP7)/ERC [322408]
- Biomedical Health Research Centre (University of Leeds)
- BBSRC CASE studentship - Avacta Analytical plc, Wetherby, UK [BB/H014713/1]
- BBSRC CASE studentship - Micromass UK Ltd./Waters Corporation, Manchester, UK [BB/I015361/1]
- BBSRC [BB/F01614X/1, BB/E012558/1]
- Biotechnology and Biological Sciences Research Council [BB/G019452/1, BB/C507029/1, 1088554, B18705, SF16972, BB/F012284/1, BB/M01259X/1, 1065203, BBS/B/04803, BB/E012558/1] Funding Source: researchfish
- Wellcome Trust [092896/Z/10/Z] Funding Source: researchfish
- BBSRC [BB/M01259X/1, BB/E012558/1] Funding Source: UKRI
- Wellcome Trust [092896/Z/10/Z] Funding Source: Wellcome Trust
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 beta-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 beta) to larger, folded immunoglobulin domains. Configured in a 48-well format, the split beta-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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