title: Unfolding and aggregation of transthyretin by the truncation of 50 N-terminal amino acids.
abstract: Senile systemic amyloidosis (SSA) is caused by amyloid deposits of wild-type transthyretin in various organs. Amyloid deposits from SSA contain large amounts of the C-terminal fragments starting near amino acid residue 50 as well as full-length transthyretin. Although a number of previous studies suggest the importance of the C-terminal fragments in the pathogenesis of SSA, little is known about the structure and aggregation properties of the C-terminal fragments of transthyretin. To understand the role of C-terminal fragments in SSA, we examined the effects of the truncation of the N-terminal portions on the structure and aggregation properties of wild-type transthyretin. The deletion mutant lacking 50 N-terminal residues was largely unfolded in terms of secondary and tertiary structure, leading to self-assembly into spherical aggregations under nearly physiological conditions. By contrast, the deletion mutant lacking 37 N-terminal residues did not have a strong tendency to aggregate, although it also adopted a largely unfolded conformation. These results suggest that global unfolding of transthyretin by proteolysis near amino acid residue 50 is an important step of self-assembly into aggregations in SSA.
authors.affiliation: Faculty of Pharmaceutical Sciences, University of Toyama, 2630 Sugitani, Toyama 930-0194, Japan. Mineyuki Mizuguchi
authors.forename: Mineyuki
authors.initials: M
authors.lastname: Mizuguchi
authors.forename: Ayumi
authors.initials: A
authors.lastname: Hayashi
authors.forename: Makoto
authors.initials: M
authors.lastname: Takeuchi
authors.forename: Mizuki
authors.initials: M
authors.lastname: Dobashi
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Mori
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Shinoda
authors.forename: Tomoyasu
authors.initials: T
authors.lastname: Aizawa
authors.forename: Makoto
authors.initials: M
authors.lastname: Demura
authors.forename: Keiichi
authors.initials: K
authors.lastname: Kawano
mesh_terms: D000596:Amino Acids / Q000235:genetics; D052160:Benzothiazoles; D002850:Chromatography, Gel; D002942:Circular Dichroism; D005453:Fluorescence; D018625:Microscopy, Atomic Force; D050505:Mutant Proteins / Q000737:chemistry; D011228:Prealbumin / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D017510:Protein Folding; D020836:Protein Structure, Quaternary; D017433:Protein Structure, Secondary; D020539:Sequence Analysis, Protein; D017384:Sequence Deletion; D013844:Thiazoles / Q000737:chemistry; D013997:Time Factors
chemical_list: D000596:Amino Acids; D052160:Benzothiazoles; D050505:Mutant Proteins; D011228:Prealbumin; D013844:Thiazoles; C009462:thioflavin T