期刊
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
卷 60, 期 20, 页码 11335-11343出版社
WILEY-V C H VERLAG GMBH
DOI: 10.1002/anie.202015988
关键词
bioconjugation; fluorescent probe; fluorescent proteins; protein aggregation; protein chemistry
资金
- National Natural Science Foundation of China [21907091]
- LiaoNing Revitalization Talents Program from the Liaoning province of China [XLYC1907048]
- Dalian Innovation Fund [2020JJ26GX027]
- China Postdoctoral Science Foundation [2019M661138]
- National Key Research and Development Program of China [2017YFA0505003]
- National Natural Science Foundation [21725506]
The study reveals that covalent Michael addition can occur during protein aggregation, offering a new pathway for chemical reactions. By designing covalent probes for imaging, chemical proteomics, and therapeutic purposes, different fluorescence color-switch responses can be achieved.
Covalent chemical reactions to modify aggregated proteins are rare. Here, we reported covalent Michael addition can generally occur upon protein aggregation. Such reactivity was initially discovered by a bioinspired fluorescent color-switch probe mimicking the photo-conversion mechanism of Kaede fluorescent protein. This probe was dark with folded proteins but turned on red fluorescence (620 nm) when it non-covalently bound to misfolded proteins. Supported by the biochemical and mass spectrometry results, the probe chemoselectively reacted with the reactive cysteines of aggregated proteins via covalent Michael addition and gradually switched to green fluorescence (515 nm) upon protein aggregation. Exploiting this Michael addition chemistry in the malachite green dye derivatives demonstrated its general applicability and chemical tunability, resulting in different fluorescence color-switch responses. Our work may offer a new avenue to explore other chemical reactions upon protein aggregation and design covalent probes for imaging, chemical proteomics, and therapeutic purposes.
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