| 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
|
| リソース情報 |
| ヒト・動物細胞 |
PC-12(RCB0009) |
