Reversible random coil-beta-sheet transition of the Alzheimer beta-amyloid fragment (25-35).
The beta-amyloid protein (39-43 amino acid residues) is the major constituent of the amyloid deposits found in brain of patients with Alzheimer's disease. Using circular dichroism spectroscopy, we have studied the secondary structure and the aggregation of fragment 25-35 of the beta-amyloid protein (beta AP(25-35)OH) under a variety of conditions. beta AP(25-35)OH in solution at pH 4.0 or 5.5 exhibits a concentration-dependent random coil<-->beta-sheet transition. The equilibrium is characterized spectroscopically by an isodichroic point and can be described quantitatively by a simple association model with association constants between 1.8 x 10(4) M-1 (non-cooperative model, nucleation parameter sigma = 1) and 2.9 x 10(4) M-1 (cooperative model, sigma = 0.2). The enthalpy of association is delta H approximately -3 kcal/mol as determined by titration calorimetry. The equilibrium is shifted completely toward beta-structured fibrils at pH 7.4 where the Met-35 carboxyl group is fully charged. In contrast, removal of the charged carboxy terminus by amidation locks the equilibrium in the random coil conformation. Model calculations suggest an antiparallel beta-sheet structure involving residues 28-35 which is stabilized at both ends of the beta-sheet by ion pairs formed between Lys-28 and Met-35. Removal of fibrils via millipore filtration leads to solutions with random coil monomers only. Seeding these solutions with a few fibrils establishes a new random coil<-->beta-sheet equilibrium.
Terzi
E
E
Department of Biophysical Chemistry, University of Basel, Switzerland.
Hölzemann
G
G
Seelig
J
J
D000544:Alzheimer Disease; D000595:Amino Acid Sequence; D016229:Amyloid beta-Peptides / Q000737:chemistry*; D002942:Circular Dichroism; D006801:Humans; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000737:chemistry*; D011487:Protein Conformation; D017433:Protein Structure, Secondary; D013816:Thermodynamics
D016229:Amyloid beta-Peptides; D010446:Peptide Fragments