title: Inhibition of beta2-microglobulin amyloid fibril formation by alpha2-macroglobulin.
abstract: The relationship between various amyloidoses and chaperones is gathering attention. In patients with dialysis-related amyloidosis, α(2)-macroglobulin (α2M), an extracellular chaperone, forms a complex with β(2)-microglobulin (β2-m), a major component of amyloid fibrils, but the molecular mechanisms and biological implications of the complex formation remain unclear. Here, we found that α2M substoichiometrically inhibited the β2-m fibril formation at a neutral pH in the presence of SDS, a model for anionic lipids. Binding analysis showed that the binding affinity between α2M and β2-m in the presence of SDS was higher than that in the absence of SDS. Importantly, SDS dissociated tetrameric α2M into dimers with increased surface hydrophobicity. Western blot analysis revealed that both tetrameric and dimeric α2M interacted with SDS-denatured β2-m. At a physiologically relevant acidic pH and in the presence of heparin, α2M was also dissociated into dimers, and both tetrameric and dimeric α2M interacted with β2-m, resulting in the inhibition of fibril growth reaction. These results suggest that under conditions where native β2-m is denatured, tetrameric α2M is also converted to dimeric form with exposed hydrophobic surfaces to favor the hydrophobic interaction with denatured β2-m, thus dimeric α2M as well as tetrameric α2M may play an important role in controlling β2-m amyloid fibril formation.
authors.affiliation: Department of Pathological Sciences, Faculty of Medical Sciences, University of Fukui, Fukui 910-1193, Japan.
authors.forename: Daisaku
authors.initials: D
authors.lastname: Ozawa
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Hasegawa
authors.forename: Young-Ho
authors.initials: YH
authors.lastname: Lee
authors.forename: Kazumasa
authors.initials: K
authors.lastname: Sakurai
authors.forename: Kotaro
authors.initials: K
authors.lastname: Yanagi
authors.forename: Tadakazu
authors.initials: T
authors.lastname: Ookoshi
authors.forename: Yuji
authors.initials: Y
authors.lastname: Goto
authors.forename: Hironobu
authors.initials: H
authors.lastname: Naiki
mesh_terms: D000510:Alpha-Globulins / Q000737:chemistry* / Q000378:metabolism; D000682:Amyloid / Q000737:chemistry* / Q000378:metabolism; D000686:Amyloidosis / Q000378:metabolism; D000818:Animals; D004970:Estrone / Q000031:analogs & derivatives; D006736:Horses; D006801:Humans; D006863:Hydrogen-Ion Concentration; D018832:Molecular Chaperones / Q000737:chemistry* / Q000378:metabolism; D046912:Multiprotein Complexes / Q000737:chemistry* / Q000378:metabolism; D011489:Protein Denaturation; D055503:Protein Multimerization; D020836:Protein Structure, Quaternary; D001613:beta 2-Microglobulin / Q000737:chemistry* / Q000378:metabolism
chemical_list: D000510:Alpha-Globulins; D000682:Amyloid; D018832:Molecular Chaperones; D046912:Multiprotein Complexes; C025500:alpha(2)-microglobulin; D001613:beta 2-Microglobulin; D004970:Estrone; C017296:estrone sulfate