title: Biophysical analyses of the transthyretin variants, Tyr114His and Tyr116Ser, associated with familial amyloidotic polyneuropathy.
abstract: The familial amyloidotic polyneuropathy is strictly associated with point mutations in the coding region of the transthyretin gene. Here, we focused on the mutations in the monomer-monomer and dimer-dimer interaction site of the transthyretin tetramer. The naturally occurring amyloidogenic Tyr114His (Y114H) and Tyr116Ser (Y116S) variants formed more amyloid fibrils than the wild-type transthyretin, nonamyloidogenic Tyr116Val (Y116V) variant, and other amyloidogenic variants in previous studies. The secondary, tertiary, and quaternary structural stabilities of the Y114H and Y116S variants were compared with those of the wild-type transthyretin and nonamyloidogenic Y116V variant. The unfolding data indicated that the amyloidogenic Y114H and Y116S mutations reduced the stability of the secondary, tertiary, and quaternary structure. Our results also indicated that the unfolding of Y114H and Y116S is less cooperative than that of the wild-type transthyretin. Moreover, the tetramer of the amyloidogenic variants dissociated to the monomer even at pH 7.0, indicating the importance of Tyr114 and Tyr116 in strengthening the contacts between monomers and/or dimers of the transthyretin molecule.
authors.affiliation: Faculty of Dental Science, Kyushu University, Fukuoka, Japan.
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Shinohara
authors.forename: Mineyuki
authors.initials: M
authors.lastname: Mizuguchi
authors.forename: Kimiaki
authors.initials: K
authors.lastname: Matsubara
authors.forename: Makoto
authors.initials: M
authors.lastname: Takeuchi
authors.forename: Atsushi
authors.initials: A
authors.lastname: Matsuura
authors.forename: Takahiro
authors.initials: T
authors.lastname: Aoki
authors.forename: Kouhei
authors.initials: K
authors.lastname: Igarashi
authors.forename: Hatsumi
authors.initials: H
authors.lastname: Nagadome
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Terada
authors.forename: Keiichi
authors.initials: K
authors.lastname: Kawano
mesh_terms: D019943:Amino Acid Substitution; D000682:Amyloid / Q000235:genetics / Q000378:metabolism; D028227:Amyloid Neuropathies, Familial / Q000235:genetics* / Q000378:metabolism*; D019281:Dimerization; D004591:Electrophoresis, Polyacrylamide Gel; D014644:Genetic Variation; D006639:Histidine / Q000235:genetics; D006801:Humans; D006863:Hydrogen-Ion Concentration; D011228:Prealbumin / Q000737:chemistry* / Q000235:genetics* / Q000378:metabolism; D020033:Protein Isoforms / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D020836:Protein Structure, Quaternary / Q000235:genetics; D012694:Serine / Q000235:genetics; D013050:Spectrometry, Fluorescence; D014364:Tryptophan / Q000737:chemistry; D014443:Tyrosine / Q000235:genetics; D014508:Urea / Q000737:chemistry
chemical_list: D000682:Amyloid; D011228:Prealbumin; D020033:Protein Isoforms; D014443:Tyrosine; D012694:Serine; D006639:Histidine; D014364:Tryptophan; D014508:Urea