Xanthone-based solvatochromic fluorophores for quantifying micropolarity of protein aggregates

Simple item page
dc.citation.firstpage12540
dc.citation.journalTitleChemical Science
dc.citation.lastpage12549
dc.citation.volumeNumber13
dc.contributor.authorWang, Lushun
dc.contributor.authorHsiung, Chia-Heng
dc.contributor.authorLiu, Xiaojing
dc.contributor.authorWang, Shichao
dc.contributor.authorLoredo, Axel
dc.contributor.authorZhang, Xin
dc.contributor.authorXiao, Han
dc.date.accessioned2022-12-13T19:11:17Z
dc.date.available2022-12-13T19:11:17Z
dc.date.issued2022
dc.description.abstractProper three-dimensional structures are essential for maintaining the functionality of proteins and for avoiding pathological consequences of improper folding. Misfolding and aggregation of proteins have been both associated with neurodegenerative disease. Therefore, a variety of fluorogenic tools that respond to both polarity and viscosity have been developed to detect protein aggregation. However, the rational design of highly sensitive fluorophores that respond solely to polarity has remained elusive. In this work, we demonstrate that electron-withdrawing heteroatoms with (d–p)–π* conjugation can stabilize lowest unoccupied molecular orbital (LUMO) energy levels and promote bathochromic shifts. Guided by computational analyses, we have devised a novel series of xanthone-based solvatochromic fluorophores that have rarely been systematically studied. The resulting probes exhibit superior sensitivity to polarity but are insensitive to viscosity. As proof of concept, we have synthesized protein targeting probes for live-cell confocal imaging intended to quantify the polarity of misfolded and aggregated proteins. Interestingly, our results reveal several layers of protein aggregates in a way that we had not anticipated. First, microenvironments with reduced polarity were validated in the misfolding and aggregation of folded globular proteins. Second, granular aggregates of AgHalo displayed a less polar environment than aggregates formed by folded globular protein represented by Htt–polyQ. Third, our studies reveal that granular protein aggregates formed in response to different types of stressors exhibit significant polarity differences. These results show that the solvatochromic fluorophores solely responsive to polarity represent a new class of indicators that can be widely used for detecting protein aggregation in live cells, thus paving the way for elucidating cellular mechanisms of protein aggregation as well as therapeutic approaches to managing intracellular aggregates.
dc.identifier.citationWang, Lushun, Hsiung, Chia-Heng, Liu, Xiaojing, et al.. "Xanthone-based solvatochromic fluorophores for quantifying micropolarity of protein aggregates." <i>Chemical Science,</i> 13, (2022) Royal Society of Chemistry: 12540-12549. https://doi.org/10.1039/D2SC05004H.
dc.identifier.digitald2sc05004h
dc.identifier.doihttps://doi.org/10.1039/D2SC05004H
dc.identifier.urihttps://hdl.handle.net/1911/114095
dc.language.isoeng
dc.publisherRoyal Society of Chemistry
dc.rightsThis Open Access Article is licensed under a Creative Commons Attribution-Non Commercial 3.0 Unported Licence
dc.rights.urihttps://creativecommons.org/licenses/by-nc/3.0/
dc.titleXanthone-based solvatochromic fluorophores for quantifying micropolarity of protein aggregates
dc.typeJournal article
dc.type.dcmiText
dc.type.publicationpublisher version
Files
Original bundle
Now showing 1 - 1 of 1
Thumbnail Image
Name:
d2sc05004h.pdf
Size:
2.24 MB
Format:
Adobe Portable Document Format
Download
Collections
Faculty Publications
Bioengineering Publications
BioSciences Publications
Chemistry Publications