Toxic Misfolded Transthyretin Oligomers with Different Molecular Conformations Formed through Distinct Oligomerization Pathways.

ABSTRACT: Protein aggregation is initiated by structural changes from native polypeptides to cytotoxic oligomers, which form cross-β structured amyloid. Identification and characterization of oligomeric intermediates are critically important for understanding not only the molecular mechanism of aggregation but also the cytotoxic nature of amyloid oligomers. Preparation of misfolded oligomers for structural characterization is, however, challenging because of their transient, heterogeneous nature. Here, we report two distinct misfolded transthyretin (TTR) oligomers formed through different oligomerization pathways. A pathogenic TTR variant with a strong aggregation propensity (L55P) was used to prepare misfolded oligomers at physiological pH. Our mechanistic studies showed that the full-length TTR in

SUBMITTER: Dasari AKR 

PROVIDER: S-EPMC9665167 | biostudies-literature | 2022 Nov

REPOSITORIES: biostudies-literature