Localized structural fluctuations promote amyloidogenic conformations in transthyretin.

ABSTRACT: The process of transthyretin (TTR) misfolding and aggregation, including amyloid formation, appears to cause a number of degenerative diseases. During amyloid formation, the native protein undergoes a tetramer-to-folded monomer transition, followed by local unfolding of the monomer to an assembly-competent amyloidogenic intermediate. Here we use NMR relaxation dispersion to probe conformational exchange at physiological pH between native monomeric TTR (the F87M/L110M variant) and a small population of a transiently formed amyloidogenic intermediate. The dispersion experiments show that a majority of the residues in the β-sheet containing β-strands D, A, G, and H undergo conformational fluctuations on microsecond-to-millisecond timescales. Exchange broadening is greatest for residues in the

SUBMITTER: Lim KH 

PROVIDER: S-EPMC3594634 | biostudies-literature | 2013 Mar

REPOSITORIES: biostudies-literature