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    Transthyretin Aggregation Pathway toward the Formation of Distinct Cytotoxic Oligomers

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    Author
    Dasari, Anvesh K. R.; Hughes, Robert M.; Wi, Sungsool; Hung, Ivan; Gan, Zhehong; Kelly, Jeffrey W.; Lim, Kwang Hun
    Abstract
    Characterization of small oligomers formed at an early stage of amyloid formation is critical to understanding molecular mechanism of pathogenic aggregation process. Here we identifed and characterized cytotoxic oligomeric intermediates populated during transthyretin (TTR) aggregation process. Under the amyloid-forming conditions, TTR initially forms a dimer through interactions between outer strands. The dimers are then associated to form a hexamer with a spherical shape, which serves as a building block to self-assemble into cytotoxic oligomers. Notably, wild-type (WT) TTR tends to form linear oligomers, while aTTR variant(G53A) prefers forming annular oligomers with pore-like structures. Structural analyses of the amyloidogenic intermediates using circular dichroism (CD) and solid-state NMR revealthatthe dimer and oligomers have a signifcant degree of native-like β-sheet structures (35–38%), but with more disordered regions (~60%)than those of nativeTTR.TheTTR variant oligomers are also less structured than WT oligomers. The partially folded nature of the oligomeric intermediates might be a common structural property of cytotoxic oligomers.The higher fexibility of the dimer and oligomers may also compensate for the entropic loss due to the oligomerization of the monomers.
    URI
    http://hdl.handle.net/10342/8343
    Date
    2019-01-10
    Citation:
    APA:
    Dasari, Anvesh K. R., & Hughes, Robert M., & Wi, Sungsool, & Hung, Ivan, & Gan, Zhehong, & Kelly, Jeffrey W., & Lim, Kwang Hun. (January 2019). Transthyretin Aggregation Pathway toward the Formation of Distinct Cytotoxic Oligomers. Scientific Reports, (9:33), p.. Retrieved from http://hdl.handle.net/10342/8343

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    MLA:
    Dasari, Anvesh K. R., and Hughes, Robert M., and Wi, Sungsool, and Hung, Ivan, and Gan, Zhehong, and Kelly, Jeffrey W., and Lim, Kwang Hun. "Transthyretin Aggregation Pathway toward the Formation of Distinct Cytotoxic Oligomers". Scientific Reports. 9:33. (.), January 2019. August 07, 2022. http://hdl.handle.net/10342/8343.
    Chicago:
    Dasari, Anvesh K. R. and Hughes, Robert M. and Wi, Sungsool and Hung, Ivan and Gan, Zhehong and Kelly, Jeffrey W. and Lim, Kwang Hun, "Transthyretin Aggregation Pathway toward the Formation of Distinct Cytotoxic Oligomers," Scientific Reports 9, no. 33 (January 2019), http://hdl.handle.net/10342/8343 (accessed August 07, 2022).
    AMA:
    Dasari, Anvesh K. R., Hughes, Robert M., Wi, Sungsool, Hung, Ivan, Gan, Zhehong, Kelly, Jeffrey W., Lim, Kwang Hun. Transthyretin Aggregation Pathway toward the Formation of Distinct Cytotoxic Oligomers. Scientific Reports. January 2019; 9(33) . http://hdl.handle.net/10342/8343. Accessed August 07, 2022.
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