2005 Fiscal Year Final Research Report Summary
Structural analysis of β-amyloid fibrils using solid-state NMR
| Project/Area Number |
16380080
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Bioproduction chemistry/Bioorganic chemistry
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| Research Institution | KYOTO UNIVERSITY |
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Principal Investigator |
IRIE Kazuhiro Kyoto University, Grad.Sch.Agric., Associate Professor, 農学研究科, 助教授 (00168535)
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| Co-Investigator(Kenkyū-buntansha) |
TAKEGOSHI Kiyonori Kyoto University, Grad.Sch.Sci., Associate Professor, 理学研究科, 助教授 (10206964)
SHIMIZU Takahiko Tokyo Metropolitan Institute of Gerontology, Department of Molecular Gerontology, Researcher, 福祉振興財団・東京都老人総合研究所分子老化研究グループ, 研究員 (40301791)
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| Project Period (FY) |
2004 – 2005
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| Keywords | Alzheimer's disease / Aβ42 / amyloid / β-sheet / aggregation / solid-state NMR / DARR / turn |
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| Research Abstract |
The aggregation of 42-mer amyloid β (Aβ42) plays a central role in the pathogenesis of Alzheimer's disease. Our recent research on the systematic replacement with proline in Aβ42 suggested that the formation of a turn structure at positions 22 and 23 could be indispensable to the 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 Lys-22 and Asp-23 in the minor conformer could be located on the same side. The data support the presence of a turn structure at positions 22 and 23 in E22K-Aβ42 fibrils. The ionic interaction between Lys-22 and Asp-23 might be a reason why E22K-Aβ42 is more aggregative and neurotoxic than wild-type Aβ42, whose residues at positions 22 and 23 are both anionic. Similar analysis of wild-type Aβ42 fibrils using solid-state NMR did not suggest that the side chains of Glu-22 and Asp-23 could be on the same side.
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[Journal Article] New aggregation model of amyloid β by the systematic proline replacement.2005
Author(s)
K.Murakami, K.Irie, A.Morimoto, Y.Masuda, H.Ohigashi, M.Nagao, H.Fukuda, T.Shimizu, T.Shirasawa
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Journal Title
In Peptide Science 2004, Shimohigashi, Y.(Ed.), The Japanese Peptide Society, Fukuoka, Japan
Pages: 179-182
Description
「研究成果報告書概要(欧文)」より
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