Transthyretin Aggregation Pathway toward the Formation of Distinct Cytotoxic Oligomers.

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 identified 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 a TTR variant (G53A) prefers forming annular oligomers with pore-like structures. Structural analyses of the amyloidogenic intermediates using circular dichroism (CD) and solid-st

SUBMITTER: Dasari AKR 

PROVIDER: S-EPMC6328637 | biostudies-literature | 2019 Jan

REPOSITORIES: biostudies-literature