A Solvatochromic Fluorescent Probe Reveals Polarity Heterogeneity upon Protein Aggregation in Cells

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  • Wang Wan
    CAS Key Laboratory of Separation Science for Analytical Chemistry Dalian Institute of Chemical Physics Chinese Academy of Sciences 457 Zhongshan Road Dalian 116023 China
  • Lianggang Zeng
    CAS Key Laboratory of Separation Science for Analytical Chemistry Dalian Institute of Chemical Physics Chinese Academy of Sciences 457 Zhongshan Road Dalian 116023 China
  • Wenhan Jin
    CAS Key Laboratory of Separation Science for Analytical Chemistry Dalian Institute of Chemical Physics Chinese Academy of Sciences 457 Zhongshan Road Dalian 116023 China
  • Xinxin Chen
    National Laboratory of Biomacromolecules CAS Center for Excellence in Biomacromolecules Institute of Biophysics Chinese Academy of Sciences 15 Datun Road, Chaoyang District Beijing 100101 China
  • Di Shen
    CAS Key Laboratory of Separation Science for Analytical Chemistry Dalian Institute of Chemical Physics Chinese Academy of Sciences 457 Zhongshan Road Dalian 116023 China
  • Yanan Huang
    CAS Key Laboratory of Separation Science for Analytical Chemistry Dalian Institute of Chemical Physics Chinese Academy of Sciences 457 Zhongshan Road Dalian 116023 China
  • Mengdie Wang
    CAS Key Laboratory of Separation Science for Analytical Chemistry Dalian Institute of Chemical Physics Chinese Academy of Sciences 457 Zhongshan Road Dalian 116023 China
  • Yulong Bai
    CAS Key Laboratory of Separation Science for Analytical Chemistry Dalian Institute of Chemical Physics Chinese Academy of Sciences 457 Zhongshan Road Dalian 116023 China
  • Haochen Lyu
    CAS Key Laboratory of Separation Science for Analytical Chemistry Dalian Institute of Chemical Physics Chinese Academy of Sciences 457 Zhongshan Road Dalian 116023 China
  • Xuepeng Dong
    The Second Hospital of Dalian Medical University 467 Zhongshan Road 116023 China Dalian
  • Zhenming Gao
    The Second Hospital of Dalian Medical University 467 Zhongshan Road 116023 China Dalian
  • Lei Wang
    National Laboratory of Biomacromolecules CAS Center for Excellence in Biomacromolecules Institute of Biophysics Chinese Academy of Sciences 15 Datun Road, Chaoyang District Beijing 100101 China
  • Xiaojing Liu
    Institute of Molecular Sciences and Engineering Shan Dong University 72 Binhai Road Qingdao 266237 China
  • Yu Liu
    CAS Key Laboratory of Separation Science for Analytical Chemistry Dalian Institute of Chemical Physics Chinese Academy of Sciences 457 Zhongshan Road Dalian 116023 China

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<jats:title>Abstract</jats:title><jats:p>We report a crystallization‐induced emission fluorophore to quantitatively interrogate the polarity of aggregated proteins. This solvatochromic probe, namely “AggRetina” probe, inherently binds to aggregated proteins and exhibits both a polarity‐dependent fluorescence emission wavelength shift and a viscosity‐dependent fluorescence intensity increase. Regulation of its polarity sensitivity was achieved by extending the conjugation length. Different proteins bear diverse polarity upon aggregation, leading to different resistance to proteolysis. Polarity primarily decreases during protein misfolding but viscosity mainly increases upon the formation of insoluble aggregates. We quantified the polarity of aggregated protein‐of‐interest in live cells via HaloTag bioorthogonal labeling, revealing polarity heterogeneity within cellular aggregates. The enriched micro‐environment details inside misfolded and aggregated proteins may correlate to their bio‐chemical properties and pathogenicity.</jats:p>

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