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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Acrylamide / chemistry
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Amino Acid Substitution / genetics
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Anilino Naphthalenesulfonates / chemistry
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Anilino Naphthalenesulfonates / metabolism
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Cell Death / drug effects
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Cell Line, Tumor
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Chromatography, Gel
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Dimerization
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Genetic Variation*
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Humans
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Isoleucine / genetics
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Microscopy, Atomic Force
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Nephelometry and Turbidimetry
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Neuroblastoma / metabolism
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Neuroblastoma / pathology
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Neurotoxins / chemistry
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Neurotoxins / genetics
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Neurotoxins / metabolism*
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Neurotoxins / toxicity
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Prealbumin / genetics
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Prealbumin / metabolism*
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Prealbumin / toxicity
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Prealbumin / ultrastructure
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Protein Binding / genetics
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Protein Conformation
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Protein Processing, Post-Translational* / genetics
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Protein Structure, Quaternary / genetics
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Protein Structure, Secondary / genetics
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Protein Structure, Tertiary / genetics
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Serine / genetics
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Spectrometry, Fluorescence / methods
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Thermodynamics
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Tryptophan / chemistry
Substances
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Anilino Naphthalenesulfonates
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Neurotoxins
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Prealbumin
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Isoleucine
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Acrylamide
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Serine
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1-anilino-8-naphthalenesulfonate
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Tryptophan