論文

査読有り
2012年2月

Positional Effects of Phosphorylation on the Stability and Morphology of Tau-Related Amyloid Fibrils

BIOCHEMISTRY
  • Masafumi Inoue
  • ,
  • Takashi Konno
  • ,
  • Kazuki Tainaka
  • ,
  • Eiji Nakata
  • ,
  • Hiro-o Yoshida
  • ,
  • Takashi Morii

51
7
開始ページ
1396
終了ページ
1406
記述言語
英語
掲載種別
研究論文(学術雑誌)
DOI
10.1021/bi201451z
出版者・発行元
AMER CHEMICAL SOC

Hyperphosphorylated forms of tau protein are the main component of paired helical filaments (PHFs) of neurofibrillary tangles in the brain of Alzheimer's disease patients. To understand the effect of phosphorylation on the fibrillation of tau, we utilized tau-derived phosphorylated peptides. The V(306)QIVYK(311) sequence (PHF6) in the microtubule-binding domain is known to play a key role in the fibrillation of tau, and the short peptide corresponding to the PHF6 sequence forms amyloid-type fibrils similar to those generated by full-length tau. We focused on the amino acid residue located at the N-terminus of the PHF6 sequence, serine or lysine in the native isoform of tau, and synthesized the PHF6 derivative peptides with serine or lysine at the N-terminus of PHF6. Peptides phosphorylated at serine and/or tyrosine were synthesized to mimic the possible phosphorylation at these positions. The critical concentrations of the fibrillation of peptides were determined to quantitatively assess fibril stability. The peptide with the net charge of near zero tended to form stable fibrils. Interestingly, the peptide phosphorylated at the N-terminal serine residue exhibited remarkably low fibrillation propensity as compared to the peptide possessing the same net charge. Transmission electron microscopy measurements of the fibrils visualized the paired helical or straight fibers and segregated masses of the fibers or heterogeneous rodlike fibers depending on the phosphorylation status. Further analyses of the fibrils by the X-ray fiber diffraction method and Fourier transform infrared spectroscopic measurements indicated that all the peptides shared a common cross-beta structure. In addition, the phosphoserine-containing peptides showed the characteristics of beta-sandwiches that could interact with both faces of the beta-sheet. On the basis of these observations, possible protofilament models with four beta-sheets were constructed to consider the positional effects of the serine and/or tyrosine phosphorylations. The electrostatic intersheet interaction between phosphate groups and the amino group of lysine enhanced the lateral association between beta-sheets to compensate for the excess charge. In addition to the previously postulated net charge of the peptide, the position of the charged residue plays a critical role in the amyloid fibrillation of tau.

Web of Science ® 被引用回数 : 15

リンク情報
DOI
https://doi.org/10.1021/bi201451z
PubMed
https://www.ncbi.nlm.nih.gov/pubmed/22304362
Web of Science
https://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcAuth=JSTA_CEL&SrcApp=J_Gate_JST&DestLinkType=FullRecord&KeyUT=WOS:000300473400008&DestApp=WOS_CPL
ID情報
  • DOI : 10.1021/bi201451z
  • ISSN : 0006-2960
  • PubMed ID : 22304362
  • Web of Science ID : WOS:000300473400008

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