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Structural Characterization of Cardiac Ex Vivo Transthyretin Amyloid: Insight into the Transthyretin Misfolding Pathway in Vivo
Name
nihms-1597587.pdf
Description
Accepted version
Size
1.03 MB
Format
Adobe PDF
Checksum (MD5)
4260960f8e94adecb7e1f63007a002cc
Journal
Biochemistry
Publisher
American Chemical Society (ACS)
Version
Author's final manuscript
Abstract
© 2020 American Chemical Society. Structural characterization of misfolded protein aggregates is essential to understanding the molecular mechanism of protein aggregation associated with various protein misfolding disorders. Here, we report structural analyses of ex vivo transthyretin aggregates extracted from human cardiac tissue. Comparative structural analyses of in vitro and ex vivo transthyretin aggregates using various biophysical techniques revealed that cardiac transthyretin amyloid has structural features similar to those of in vitro transthyretin amyloid. Our solid-state nuclear magnetic resonance studies showed that in vitro amyloid contains extensive nativelike β-sheet structures, while other loop regions including helical structures are disrupted in the amyloid state. These results suggest that transthyretin undergoes a common misfolding and aggregation transition to nativelike aggregation-prone monomers that self-assemble into amyloid precipitates in vitro and in vivo.
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Creative Commons Attribution-Noncommercial-Share Alike
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DOI of Published Version
10.1021/acs.biochem.0c00091
