Verification of the turn at positions 22 and 23 of the beta-amyloid fibrils with Italian mutation using solid-state NMR.
The aggregation of 42-mer amyloid beta (Abeta42) plays a central role in the pathogenesis of Alzheimer's disease. Our recent research on proline mutagenesis of Abeta42 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-Abeta42 (Italian mutation) aggregated more rapidly and with more potent neurotoxicity than wild-type Abeta42, the tertiary structure at positions 21-24 of E22K-Abeta42 fibrils was analyzed by solid-state NMR using dipolar-assisted rotational resonance (DARR) to identify the 'malignant' conformation of Abeta42. 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-Abeta42 fibrils. The formation of a salt bridge between Lys-22 and Asp-23 in the minor conformer might be a reason why E22K-Abeta42 is more pathogenic than wild-type Abeta42.
Masuda
Yuichi
Y
Division of Food Science and Biotechnology, Graduate School of Agriculture, Kyoto University, Sakyo-ku, Kyoto 606-8502, Japan.
Irie
Kazuhiro
K
Murakami
Kazuma
K
Ohigashi
Hajime
H
Ohashi
Ryutaro
R
Takegoshi
K
K
Shimizu
Takahiko
T
Shirasawa
Takuji
T
D000595:Amino Acid Sequence; D000682:Amyloid / Q000737:chemistry*; D016229:Amyloid beta-Peptides / Q000737:chemistry* / Q000235:genetics* / Q000648:ultrastructure; D018698:Glutamic Acid / Q000235:genetics; D006801:Humans; D007558:Italy; D009682:Magnetic Resonance Spectroscopy; D046529:Microscopy, Electron, Transmission; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics*; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid
D000682:Amyloid; D016229:Amyloid beta-Peptides; D018698:Glutamic Acid