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J Am Chem Soc. 2018 Jun 20;140(24):7381-7384. doi: 10.1021/jacs.8b02176. Epub 2018 Jun 12.

Modulation of Fluorescent Protein Chromophores To Detect Protein Aggregation with Turn-On Fluorescence.

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Department of Chemistry , University of Washington , Seattle , Washington 98105 , United States.


We present a fluorogenic method to visualize misfolding and aggregation of a specific protein-of-interest in live cells using structurally modulated fluorescent protein chromophores. Combining photophysical analysis, X-ray crystallography, and theoretical calculation, we show that fluorescence is triggered by inhibition of twisted-intramolecular charge transfer of these fluorophores in the rigid microenvironment of viscous solvent or protein aggregates. Bioorthogonal conjugation of the fluorophore to Halo-tag fused protein-of-interests allows for fluorogenic detection of both misfolded and aggregated species in live cells. Unlike other methods, our method is capable of detecting previously invisible misfolded soluble proteins. This work provides the first application of fluorescent protein chromophores to detect protein conformational collapse in live cells.

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