論文

査読有り 国際誌
2020年5月5日

Amyloid Formation of α-Synuclein Based on the Solubility- and Supersaturation-Dependent Mechanism.

Langmuir : the ACS journal of surfaces and colloids
  • Maya Sawada
  • ,
  • Keiichi Yamaguchi
  • ,
  • Miki Hirano
  • ,
  • Masahiro Noji
  • ,
  • Masatomo So
  • ,
  • Daniel Otzen
  • ,
  • Yasushi Kawata
  • ,
  • Yuji Goto

36
17
開始ページ
4671
終了ページ
4681
記述言語
英語
掲載種別
研究論文(学術雑誌)
DOI
10.1021/acs.langmuir.0c00426

Amyloid fibrils are formed by denatured proteins when the supersaturation of denatured proteins is broken by agitation, such as ultrasonication, or by seeding, although the detailed mechanism of how solubility and supersaturation regulate amyloid formation remains unclear. To further understand the mechanism of amyloid formation, we examined α-synuclein (α-syn) amyloid formation at varying concentrations of SDS, LPA, heparin, or NaCl at pH 7.5. Amyloid fibrils were formed below or around the critical micelle concentrations (CMCs) of SDS (2.75 mM) and LPA (0.24 mM), although no fibrils were formed above the CMCs. On the other hand, amyloid fibrils were formed with 0.01-2.5 mg/mL of heparin and 0.5-1.0 M NaCl, and amyloid formation was gradually suppressed at higher concentrations of heparin and NaCl. To reproduce these concentration-dependent effects of additives, we constructed two models: (i) the ligand-binding-dependent solubility-modulation model and (ii) the cosolute-dependent direct solubility-modulation model, both of which were used by Tanford and colleagues to analyze the additive-dependent conformational transitions of proteins. The solubility of α-syn was assumed to vary depending on the concentration of additives either by the decreased solubility of the additive-α-syn complex (model i) or by the direct regulation of α-syn solubility (model ii). Both models well reproduced additive-dependent bell-shaped profiles of acceleration and inhibition observed for SDS and LPA. As for heparin and NaCl, participation of amorphous aggregates at high concentrations of additives was suggested. The models confirmed that solubility and supersaturation play major roles in driving amyloid formation in vitro, furthering our understanding of the pathogenesis of amyloidosis in vivo.

リンク情報
DOI
https://doi.org/10.1021/acs.langmuir.0c00426
PubMed
https://www.ncbi.nlm.nih.gov/pubmed/32271585

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