title: Assemblies of Alzheimer's peptides A beta 25-35 and A beta 31-35: reverse-turn conformation and side-chain interactions revealed by X-ray diffraction.
abstract: Alzheimer's beta amyloid protein (A beta) 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 (A beta 25-35), 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 A beta 25-35 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 A beta 31-35 (Ile-Ile-Gly-Leu-Met) and tachykinin analogue A beta(Phe(31))31-35 (Phe-Ile-Gly-Leu-Met) gave powder diffraction patterns to 2.8A Bragg spacing. The observed reflections were indexed by an orthogonal unit cell having dimensions of a=9.36 A, b=15.83 A, and c=20.10 A for the native A beta 31-35 peptide, and a=9.46 A, b=16.22 A, and c=11.06 A for the peptide having the Ile31Phe 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 P require a reverse turn, and that A beta is cytotoxic when it is oligomeric or fibrillar, we propose that the tachykinin-like A beta 31-35 domain is a turn exposed at the A beta oligomer surface where it could interact with the ligand-binding site of the tachykinin G-protein-coupled receptor.
authors.affiliation: Department of Biology, Higgins Hall, Boston College, Chestnut Hill, MA 02467, USA.
authors.forename: Jeremy P
authors.initials: JP
authors.lastname: Bond
authors.forename: Sean P
authors.initials: SP
authors.lastname: Deverin
authors.forename: Hideyo
authors.initials: H
authors.lastname: Inouye
authors.forename: Omar M A
authors.initials: OM
authors.lastname: el-Agnaf
authors.forename: Martha M
authors.initials: MM
authors.lastname: Teeter
authors.forename: Daniel A
authors.initials: DA
authors.lastname: Kirschner
mesh_terms: D000596:Amino Acids / Q000737:chemistry; D016229:Amyloid beta-Peptides / Q000737:chemistry*; D001665:Binding Sites; D004583:Electrons; D005583:Fourier Analysis; D006801:Humans; D006860:Hydrogen Bonding; D008024:Ligands; D008854:Microscopy, Electron; D008958:Models, Molecular; D010452:Peptide Biosynthesis; D010446:Peptide Fragments / Q000737:chemistry*; D010455:Peptides / Q000737:chemistry; D011485:Protein Binding; D011487:Protein Conformation; D017433:Protein Structure, Secondary; D015320:Tachykinins / Q000737:chemistry; D014961:X-Ray Diffraction / Q000379:methods*
chemical_list: D000596:Amino Acids; D016229:Amyloid beta-Peptides; D008024:Ligands; D010446:Peptide Fragments; D010455:Peptides; D015320:Tachykinins; C074636:amyloid beta-protein (25-35); C113042:amyloid beta-protein (31-35)