title: Different disease-causing mutations in transthyretin trigger the same conformational conversion.
abstract: Transthyretin (TTR)-containing amyloid fibrils are deposited in cardiac tissue as a natural consequence of aging. A large number of inherited mutations lead to amyloid diseases by accelerating TTR deposition in other organs. Amyloid formation is preceded by a disruption of the quaternary structure of TTR and conformational changes in the monomer. To study conformational changes preceding the formation of amyloid, we performed molecular dynamics simulations of the wild-type monomer, amyloidogenic variants (V30M, L55P, V122I) and a protective variant (T119M) at neutral and low pH. At low pH, the D strand dissociated from the beta-sheet to expose the A strand, consistent with experimental studies. In amyloidogenic variants and in the wild-type at low pH, there was a conformational change in the beta-sheets into alpha-sheet via peptide bond flips that was not observed at neutral pH in the wild-type monomer. The same residues participated in conversion in each amyloidogenic variant simulation, originating in the G strand between residues 106 and 109, with accelerated conversion at low pH. The T119M protective variant changed the local conformation of the H strand and suppressed the conversion observed in amyloidogenic variants.
authors.affiliation: Department of Bioengineering, University of Washington, Seattle, WA 98195-5061, USA.
authors.forename: Robert E
authors.initials: RE
authors.lastname: Steward
authors.forename: Roger S
authors.initials: RS
authors.lastname: Armen
authors.forename: Valerie
authors.initials: V
authors.lastname: Daggett
mesh_terms: D000595:Amino Acid Sequence; D017772:Amyloid Neuropathies / Q000235:genetics*; D006801:Humans; D006860:Hydrogen Bonding; D006863:Hydrogen-Ion Concentration; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009154:Mutation; D011228:Prealbumin / Q000737:chemistry* / Q000235:genetics*; D011487:Protein Conformation; D017510:Protein Folding
chemical_list: D011228:Prealbumin