論文

査読有り
2008年11月

Charge-Pairing Mechanism of Phosphorylation Effect upon Amyloid Fibrillation of Human Tau Core Peptide

BIOCHEMISTRY
  • Masafumi Inoue
  • ,
  • Akiyoshi Hirata
  • ,
  • Kazuki Tainaka
  • ,
  • Takashi Morii
  • ,
  • Takashi Konno

47
45
開始ページ
11847
終了ページ
11857
記述言語
英語
掲載種別
研究論文(学術雑誌)
DOI
10.1021/bi8010994
出版者・発行元
AMER CHEMICAL SOC

Phosphorylation of a fibrillogenic protein, human tau, is believed to play crucial roles in the pathogenesis of Alzheimer's disease. For elucidating molecular mechanisms of the phosphorylation effect on tau fibrillation, we synthesized a peptide, VQTVY(310)K (PHF6) and its phosphorylated derivative (PHF(6)pY). PHF6 is a partial peptide surrounding a plausible in vivo phosphorylation site Tyr310 and forms amyloid-type fibrils similar to those generated by full-length tau. Fibrillation of PHF6 and PHF6pY were studied by spectroscopic and microscopic methods, and the critical concentration of the fibrillation was determined for comparing the fibril stability. The results showed that the phosphorylation strongly influenced the fibrillation propensity of PHF6 by changing its dependency on pH and ionic strength. On the basis of the observations, we suggested that charged sites on the phosphate group and its electrostatic pairing with the neighboring charged residues were physical origins of the phosphorylation effect. To verify this charge-pairing mechanism, we conducted experiments using a series of PHF6 derivatives with non-native charge distributions. The electrostatic interaction in an intermolecular mode was also demonstrated by the system composed of two different peptide species, which found that fibrillation of nonphosphorylated PHF6 was drastically enhanced when a trace amount of phosphorylated PHF6 molecules coexisted. A simulation analysis utilizing crystal coordinates of the PHF6 fibril was also performed for interpreting the experimental results in a molecular level. The present study using the model peptide system gave us a microscopically insightful view on the roles of tau phosphorylation in amyloid-related diseases.

Web of Science ® 被引用回数 : 12

リンク情報
DOI
https://doi.org/10.1021/bi8010994
PubMed
https://www.ncbi.nlm.nih.gov/pubmed/18922026
Web of Science
https://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcAuth=JSTA_CEL&SrcApp=J_Gate_JST&DestLinkType=FullRecord&KeyUT=WOS:000260616900017&DestApp=WOS_CPL
ID情報
  • DOI : 10.1021/bi8010994
  • ISSN : 0006-2960
  • PubMed ID : 18922026
  • Web of Science ID : WOS:000260616900017

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