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    Michler’s hydrol blue elucidates structural differences in prion strains

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    Type
    Article
    Authors
    Xiao, Yiling
    Rocha, Sandra
    Kitts, Catherine C.
    Reymer, Anna
    Beke-Somfai, Tamás
    Frederick, Kendra K.
    Nordén, Bengt
    KAUST Grant Number
    KUK-11-008-23
    Date
    2020-11-09
    Embargo End Date
    2021-05-10
    Permanent link to this record
    http://hdl.handle.net/10754/665949
    
    Metadata
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    Abstract
    Yeast prions provide self-templating protein-based mechanisms of inheritance whose conformational changes lead to the acquisition of diverse new phenotypes. The best studied of these is the prion domain (NM) of Sup35, which forms an amyloid that can adopt several distinct conformations (strains) that confer distinct phenotypes when introduced into cells that do not carry the prion. Classic dyes, such as thioflavin T and Congo red, exhibit large increases in fluorescence when bound to amyloids, but these dyes are not sensitive to local structural differences that distinguish amyloid strains. Here we describe the use of Michler’s hydrol blue (MHB) to investigate fibrils formed by the weak and strong prion fibrils of Sup35NM and find that MHB differentiates between these two polymorphs. Quantum mechanical time-dependent density functional theory (TDDFT) calculations indicate that the fluorescence properties of amyloid-bound MHB can be correlated to the change of binding site polarity and that a tyrosine to phenylalanine substitution at a binding site could be detected. Through the use of site-specific mutants, we demonstrate that MHB is a site-specific environmentally sensitive probe that can provide structural details about amyloid fibrils and their polymorphs.
    Citation
    Xiao, Y., Rocha, S., Kitts, C. C., Reymer, A., Beke-Somfai, T., Frederick, K. K., & Nordén, B. (2020). Michler’s hydrol blue elucidates structural differences in prion strains. Proceedings of the National Academy of Sciences, 202001732. doi:10.1073/pnas.2001732117
    Sponsors
    The late Professor Susan Lindquist was involved in the initiation of this project and the authors acknowledge (and miss) her scientific insight and enthusiasm. King Abdullah University of Science and Technology (Grant KUK-11-008-23) is gratefully acknowledged. We give special thanks to Johan Johansson for assessing the purity of the Michler’s hydrol blue sample used in these experiments. Swedish National Infrastructure for Computing resources were used for the quantum mechanics calculations. This work was supported by grants from NSF (Grant 1751174), the Welch Foundation (Grant 1-1923-20170325), NIH (Grant NS-111236), the Cancer Prevention & Research Institute of Texas (Grant RR150076), the Lupe Murchison Foundation, and the Kinship Foundation (Searle Scholars Program) (all to K.K.F.). Support from the Hungarian Academy of Science within the Momentum Programme (Grant LP2016-2) is also acknowledged.
    Publisher
    Proceedings of the National Academy of Sciences
    Journal
    Proceedings of the National Academy of Sciences
    DOI
    10.1073/pnas.2001732117
    Additional Links
    http://www.pnas.org/lookup/doi/10.1073/pnas.2001732117
    ae974a485f413a2113503eed53cd6c53
    10.1073/pnas.2001732117
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