論文 - 詳細
| RRC ID | 42235 |
|---|---|
| 著者 | Morimoto A, Irie K, Murakami K, Masuda Y, Ohigashi H, Nagao M, Fukuda H, Shimizu T, Shirasawa T. |
| タイトル | Analysis of the secondary structure of beta-amyloid (Abeta42) fibrils by systematic proline replacement. |
| ジャーナル | J Biol Chem |
| Abstract |
Amyloid fibrils in Alzheimer's disease mainly consist of 40- and 42-mer beta-amyloid peptides (Abeta40 and Abeta42) that exhibit aggregative ability and neurotoxicity. Although the aggregates of Abeta peptides are rich in intermolecular beta-sheet, the precise secondary structure of Abeta in the aggregates remains unclear. To identify the amino acid residues involved in the beta-sheet formation, 34 proline-substituted mutants of Abeta42 were synthesized and their aggregative ability and neurotoxicity on PC12 cells were examined. Prolines are rarely present in beta-sheet, whereas they are easily accommodated in beta-turn as a Pro-X corner. Among the mutants at positions 15-32, only E22P-Abeta42 extensively aggregated with stronger neurotoxicity than wild-type Abeta42, suggesting that the residues at positions 15-21 and 24-32 are involved in the beta-sheet and that the turn at positions 22 and 23 plays a crucial role in the aggregation and neurotoxicity of Abeta42. The C-terminal proline mutants (A42P-, I41P-, and V40P-Abeta42) hardly aggregated with extremely weak cytotoxicity, whereas the C-terminal threonine mutants (A42T- and I41T-Abeta42) aggregated potently with significant cytotoxicity. These results indicate that the hydrophobicity of the C-terminal two residues of Abeta42 is not related to its aggregative ability and neurotoxicity, rather the C-terminal three residues adopt the beta-sheet. These results demonstrate well the large difference in aggregative ability and neurotoxicity between Abeta42 and Abeta40. In contrast, the proline mutants at the N-terminal 13 residues showed potent aggregative ability and neurotoxicity similar to those of wild-type Abeta42. The identification of the beta-sheet region of Abeta42 is a basis for designing new aggregation inhibitors of Abeta peptides. |
| 巻・号 | 279(50) |
| ページ | 52781-8 |
| 公開日 | 2004-12-10 |
| DOI | 10.1074/jbc.M406262200 |
| PII | S0021-9258(20)67726-2 |
| PMID | 15459202 |
| MeSH | Alzheimer Disease / etiology Alzheimer Disease / metabolism Amino Acid Sequence Amino Acid Substitution Amyloid beta-Peptides / chemistry* Amyloid beta-Peptides / genetics Humans Hydrophobic and Hydrophilic Interactions In Vitro Techniques Microscopy, Electron Models, Molecular Molecular Sequence Data Multiprotein Complexes Mutagenesis Peptide Fragments / chemistry* Peptide Fragments / genetics Proline / chemistry Protein Structure, Secondary Recombinant Proteins / chemistry Recombinant Proteins / genetics |
| IF | 4.238 |
| 引用数 | 128 |
| WOS 分野 | BIOCHEMISTRY & MOLECULAR BIOLOGY |
| オルトメトリクス指標 |
オルトメトリクス指標項目
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| 最多言及媒体 | Patent(IFI CLAIMS) |
| 各媒体での言及数の合計 | 9 |
| 過去6か月間でのオルトメトリクス指標の変動値 | 3.0 |
| リソース情報 | |
| ヒト・動物細胞 | PC-12(RCB0009) |