NMR Research Today is a free monthly online journal that collates and summarizes the latest research about NMR, including details on nuclear magnetic resonance, structural determination, techniques.

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

Masuda Y, Irie K, Murakami K, Ohigashi H, Ohashi R, Takegoshi K, Shimizu T, Shirasawa T

Division of Food Science and Biotechnology, Graduate School of Agriculture, Kyoto University, Sakyo-ku, Kyoto 606-8502, Japan.

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.

Published 7 November 2005 in Bioorg Med Chem, 13(24): 6803-9.
Full-text of this article is available online (may require subscription).

© 2005-2008 NMR Research Today. All Rights Reserved.