論文

査読有り 国際誌
2020年2月

The Route from the Folded to the Amyloid State: Exploring the Potential Energy Surface of a Drug-Like Miniprotein

CHEMISTRY-A EUROPEAN JOURNAL
  • Taricska, Nora
  • ,
  • Horvath, Daniel
  • ,
  • Menyhard, Dora K.
  • ,
  • Akontz-Kiss, Hanna
  • ,
  • Noji, Masahiro
  • ,
  • So, Masatomo
  • ,
  • Goto, Yuji
  • ,
  • Fujiwara, Toshimichi
  • ,
  • Perczel, Andras

26
9
開始ページ
1968
終了ページ
1978
記述言語
英語
掲載種別
研究論文(学術雑誌)
DOI
10.1002/chem.201903826
出版者・発行元
WILEY-V C H VERLAG GMBH

The amyloid formation of the folded segment of a variant of Exenatide (a marketed drug for type-2 diabetes mellitus) was studied by electronic circular dichroism (ECD) and NMR spectroscopy. We found that the optimum temperature for E5 protein amyloidosis coincides with body temperature and requires well below physiological salt concentration. Decomposition of the ECD spectra and its barycentric representation on the folded-unfolded-amyloid potential energy surface allowed us to monitor the full range of molecular transformation of amyloidogenesis. We identified points of no return (e.g.; T=37 degrees C, pH 4.1, c(E5)=250 mu m, c(NaCl)=50 mm, t>4-6 h) that will inevitably gravitate into the amyloid state. The strong B-type far ultraviolet (FUV)-ECD spectra and an unexpectedly strong near ultraviolet (NUV)-ECD signal (Theta(approximate to 275-285) (nm)) indicate that the amyloid phase of E5 is built from monomers of quasi-elongated backbone structure (phi approximate to-145 degrees, psi approximate to+145 degrees) with strong interstrand Tyr <-> Trp interaction. Misfolded intermediates and the buildup of "toxic" early-stage oligomers leading to self-association were identified and monitored as a function of time. Results indicate that the amyloid transition is triggered by subtle misfolding of the alpha-helix, exposing aromatic and hydrophobic side chains that may provide the first centers for an intermolecular reorganization. These initial clusters provide the spatial closeness and sufficient time for a transition to the beta-structured amyloid nucleus, thus the process follows a nucleated growth mechanism.

Web of Science ® 被引用回数 : 1

リンク情報
DOI
https://doi.org/10.1002/chem.201903826
PubMed
https://www.ncbi.nlm.nih.gov/pubmed/31647140
PubMed Central
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7028080
Web of Science
https://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcAuth=JSTA_CEL&SrcApp=J_Gate_JST&DestLinkType=FullRecord&KeyUT=WOS:000504516700001&DestApp=WOS_CPL

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