Verification of the turn at positions 22 and 23 of the β-amyloid fibrils with Italian mutation using solid-state NMR

Yuichi Masuda, Kazuhiro Irie, Kazuma Murakami, Hajime Ohigashi, Ryutaro Ohashi, K. Takegoshi, Takahiko Shimizu, Takuji Shirasawa

Research output: Contribution to journalArticle

30 Citations (Scopus)

Abstract

The aggregation of 42-mer amyloid β (Aβ42) plays a central role in the pathogenesis of Alzheimer's disease. Our recent research on proline mutagenesis of Aβ42 suggested that the formation of a turn structure at positions 22 and 23 could play a crucial role in its aggregative ability and neurotoxicity. Since E22K-Aβ42 (Italian mutation) aggregated more rapidly and with more potent neurotoxicity than wild-type Aβ42, the tertiary structure at positions 21-24 of E22K-Aβ42 fibrils was analyzed by solid-state NMR using dipolar-assisted rotational resonance (DARR) to identify the 'malignant' conformation of Aβ42. Two sets of chemical shifts for Asp-23 were observed in a ratio of about 2.6:1. The 2D DARR spectra at the mixing time of 500 ms suggested that the side chains of Asp-23 and Val-24 in the major conformer, and those of Lys-22 and Asp-23 in the minor conformer could be located on the same side, respectively. These data support the presence of a turn structure at positions 22 and 23 in E22K-Aβ42 fibrils. The formation of a salt bridge between Lys-22 and Asp-23 in the minor conformer might be a reason why E22K-Aβ42 is more pathogenic than wild-type Aβ42.

Original languageEnglish
Pages (from-to)6803-6809
Number of pages7
JournalBioorganic and Medicinal Chemistry
Volume13
Issue number24
DOIs
Publication statusPublished - 2005 Dec 15

Keywords

  • Amyloid β
  • Italian mutation
  • Solid-state NMR
  • Turn

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmaceutical Science
  • Drug Discovery
  • Clinical Biochemistry
  • Organic Chemistry

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    Masuda, Y., Irie, K., Murakami, K., Ohigashi, H., Ohashi, R., Takegoshi, K., Shimizu, T., & Shirasawa, T. (2005). Verification of the turn at positions 22 and 23 of the β-amyloid fibrils with Italian mutation using solid-state NMR. Bioorganic and Medicinal Chemistry, 13(24), 6803-6809. https://doi.org/10.1016/j.bmc.2005.07.071