Assemblies of Alzheimer's peptides Aβ25-35 and Aβ31-35:: reverse-turn conformation and side-chain interactions revealed by X-ray diffraction

Alzheimer's beta amyloid protein (Abeta) is a 39 to 43 amino acid peptide that is a major component in the neuritic plaques of Alzheimer's disease (AD). The assemblies constituted from residues 25-35 (Abeta25-35), which is a sequence homologous to the tachykinin or neurokinin class of neuropeptides, are neurotoxic. We used X-ray diffraction and electron microscopy to investigate the structure of the assemblies formed by Abeta25-35 peptides and of various length sequences therein, and of tachykinin-like analogues. Most solubilized peptides after subsequent drying produced diffraction patterns characteristic of beta-sheet structure. Moreover, the peptides Abeta31-35 (Ile-Ile-Gly-Leu-Met) and tachykinin analogue Abeta(Phe(31))31-35 (Phe-Ile-Gly-Leu-Met) gave powder diffraction patterns to 2.8 Angstrom Bragg spacing. The observed reflections were indexed by an orthogonal unit cell having dimensions of a = 9.36 Angstrom, b = 15.83 Angstrom, and c = 20.10 Angstrom for the native Abeta31-35 peptide, and a = 9.46 Angstrom, b = 16.22 Angstrom, and c = 11.06 Angstrom for the peptide having the Ile31 Phe substitution. The initial model was a beta strand where the hydrogen bonding, chain, and intersheet directions were placed along the a, b, and c axes. An atomic model was fit to the electron density distribution, and subsequent refinement resulted in R factors of 0.27 and 0.26, respectively. Both peptides showed a reverse turn at Gly33 which results in intramolecular hydrogen bonding between the antiparallel chains. Based on previous reports that antagonists for the tachykinin substance beta require a reverse turn, and that Abeta is cytotoxic when it is oligorneric or fibrillar, we propose that the tachykinin-like Abeta31-35 domain is a turn exposed at the Abeta oligomer surface where it could interact with the ligand-binding site of the tachykinin G-protein-coupled receptor. (C) 2003 Elsevier Science (USA). All rights reserved.