title: Specific disruption of transthyretin(105-115) fibrilization using "stabilizing" inhibitors of transthyretin amyloidogenesis.
abstract: Transthyretin (TTR) is a cerebrospinal fluid and serum protein that undergoes ordered aggregation (amyloidogenesis) in familial amyloidotic polyneuropathy (FAP) and senile systemic amyloidosis (SSA). It is now widely accepted that dissociation of the native TTR tetramer is a precondition for amyloidogenesis; thus, molecules that stabilize the tetramer have received much attention as potential TTR amyloidosis inhibitors. Many of these inhibitors bind to the thyroxine (T(4)) binding pocket and interact specifically with a section of the TTR sequence, corresponding to residues 105-115, that is implicated in amyloidogenic propensity. In this work, we study the effects of "stabilizing" inhibitors on ordered aggregation of TTR(105-115) peptide. We show that molecules known to bind full-length TTR at the T(4) site are potent, specific inhibitors of ordered aggregation, while molecules that do not interact with TTR exhibit milder, nonspecific disruption through a "hyperbundling" effect. Our results suggest that, in addition to annealing the native tetramer, "stabilizing" inhibitors may also directly disrupt amyloidogenic aggregation of TTR monomers through specific interactions with the exposed TTR(105-115) sequence.
authors.affiliation: Department of Chemistry, York University, Toronto, Ontario M3J 1P3, Canada.
authors.forename: Yanfang
authors.initials: Y
authors.lastname: Liang
authors.forename: Moriam O
authors.initials: MO
authors.lastname: Ore
authors.forename: Sylvie
authors.initials: S
authors.lastname: Morin
authors.forename: Derek J
authors.initials: DJ
authors.lastname: Wilson
mesh_terms: D000682:Amyloid / Q000737:chemistry* / Q000378:metabolism; D028227:Amyloid Neuropathies, Familial / Q000378:metabolism; D000686:Amyloidosis / Q000378:metabolism*; D006801:Humans; D007700:Kinetics; D010455:Peptides / Q000737:chemistry / Q000378:metabolism; D011228:Prealbumin / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000378:metabolism; D017510:Protein Folding
chemical_list: D000682:Amyloid; D010455:Peptides; D011228:Prealbumin