Two-dimensional structure of beta-amyloid(10-35) fibrils

beta-Amyloid (A beta) peptides are the main protein component of the pathog nomonic plaques found in the brains of patients with Alzheimer's disease. T hese heterogeneous peptides adopt a highly organized fibril structure both in vivo and in vitro. Here we use solid-state NMR on stable, homogeneous fi brils of A beta((10-35)) Specific interpeptide distance constraints are det ermined with dipolar recoupling NMR on Fibrils prepared from a series of si ngly labeled peptides containing C-13-carbonyl-enriched amino acids, and sk ipping no more that three residues in the sequence. From these studies, we demonstrate that the peptide adopts the structure of an extended parallel b eta-sheet in-register at pH 7.4. Analysis of DRAWS data indicates interstra nd distances of 5.3 +/- 0.3 Angstrom (mean +/- standard deviation) througho ut the entire length of the peptide, which is compatible only with a parall el beta-strand in-register. Intrastrand NMR constraints, obtained from pept ides containing labels at two adjacent amino acids, confirm the secondary s tructural findings obtained using DRAWS. Using peptides with C-13 incorpora ted at the carbonyl position of adjacent amino acids, structural transition s from alpha-helix to beta-sheet were observed at residues 19 and 20, but u sing similar techniques, no evidence for a turn could be found in the putat ive turn region comprising residues 25-29, Implications of this extended pa rallel organization for A beta((10-35)) for overall fibril formation, stabi lity, and morphology based upon specific amino acid contacts are discussed.