title: Dimeric transthyretin variant assembles into spherical neurotoxins.
abstract: Familial amyloidotic polyneuropathy is a hereditary autosomal-dominant disease in which the deposited transthyretin fibrils are derived from amyloidogenic mutation. We investigated structure and stability of a human Ser112Ile transthyretin variant and showed that the Ser112Ile variant exists as a dimer having nonnative tertiary structure at physiological pH. In addition, the dimeric Ser112Ile assembles into a spherical aggregate and exerts cytotoxicity in a human neuroblastoma cell line. Our results suggest the importance of an unstable dimeric structure in forming spherical aggregates that will induce cell death.
authors.affiliation: Faculty of Pharmaceutical Sciences, Toyama Medical and Pharmaceutical University, Toyama 930-0194, Japan.
authors.forename: Kimiaki
authors.initials: K
authors.lastname: Matsubara
authors.forename: Mineyuki
authors.initials: M
authors.lastname: Mizuguchi
authors.forename: Kouhei
authors.initials: K
authors.lastname: Igarashi
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Shinohara
authors.forename: Makoto
authors.initials: M
authors.lastname: Takeuchi
authors.forename: Atsushi
authors.initials: A
authors.lastname: Matsuura
authors.forename: Takayuki
authors.initials: T
authors.lastname: Saitoh
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Mori
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Shinoda
authors.forename: Keiichi
authors.initials: K
authors.lastname: Kawano
mesh_terms: D020106:Acrylamide / Q000737:chemistry; D019943:Amino Acid Substitution / Q000235:genetics; D000817:Anilino Naphthalenesulfonates / Q000737:chemistry / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D002850:Chromatography, Gel; D019281:Dimerization; D014644:Genetic Variation; D006801:Humans; D007532:Isoleucine / Q000235:genetics; D018625:Microscopy, Atomic Force; D009391:Nephelometry and Turbidimetry; D009447:Neuroblastoma / Q000378:metabolism / Q000473:pathology; D009498:Neurotoxins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism* / Q000633:toxicity; D011228:Prealbumin / Q000235:genetics / Q000378:metabolism* / Q000633:toxicity / Q000648:ultrastructure; D011485:Protein Binding / Q000235:genetics; D011487:Protein Conformation; D011499:Protein Processing, Post-Translational / Q000235:genetics; D020836:Protein Structure, Quaternary / Q000235:genetics; D017433:Protein Structure, Secondary / Q000235:genetics; D017434:Protein Structure, Tertiary / Q000235:genetics; D012694:Serine / Q000235:genetics; D013050:Spectrometry, Fluorescence / Q000379:methods; D013816:Thermodynamics; D014364:Tryptophan / Q000737:chemistry
chemical_list: D000817:Anilino Naphthalenesulfonates; D009498:Neurotoxins; D011228:Prealbumin; D007532:Isoleucine; D020106:Acrylamide; D012694:Serine; C027132:1-anilino-8-naphthalenesulfonate; D014364:Tryptophan