A transthyretin monomer intermediate undergoes local unfolding and transient interaction with oligomers in a kinetically concerted aggregation pathway.

ABSTRACT: Transthyretin (TTR) amyloidosis is associated with tissue deposition of TTR aggregates. TTR aggregation is initiated by dissociation of the native tetramer to form a monomeric intermediate, which locally unfolds and assembles into soluble oligomers and higher-order aggregates. However, a detailed mechanistic understanding requires kinetic and structural characterization of the low population intermediates formed. Here, we show that the monomeric intermediate exchanges with an ensemble of oligomers on the millisecond timescale. This transient and reversible exchange causes broadening of the ¹⁹F resonance of a trifluoromethyl probe coupled to the monomeric intermediate at S85C. We show the ¹⁹F linewidth and R₂ relaxation rate increase with increasing concentr

SUBMITTER: Sun X 

PROVIDER: S-EPMC9293765 | biostudies-literature | 2022 Aug

REPOSITORIES: biostudies-literature