Solution structure of methionine-oxidized amyloid beta-peptide (1-40). Does oxidation affect conformational switching?
The solution structure of Abeta(1-40)Met(O), the methionine-oxidized form of amyloid beta-peptide Abeta(1-40), has been investigated by CD and NMR spectroscopy. Oxidation of Met35 may have implications in the aetiology of Alzheimer's disease. Circular dichroism experiments showed that whereas Abeta(1-40) and Abeta(1-40)Met(O) both adopt essentially random coil structures in water (pH 4) at micromolar concentrations, the former aggregates within several days while the latter is stable for at least 7 days under these conditions. This remarkable difference led us to determine the solution structure of Abeta(1-40)Met(O) using 1H NMR spectroscopy. In a water-SDS micelle medium needed to solubilize both peptides at the millimolar concentrations required to measure NMR spectra, chemical shift and NOE data for Abeta(1-40)Met(O) strongly suggest the presence of a helical region between residues 16 and 24. This is supported by slow H-D exchange of amide protons in this region and by structure calculations using simulated annealing with the program XPLOR. The remainder of the structure is relatively disordered. Our previously reported NMR data for Abeta(1-40) in the same solvent shows that helices are present over residues 15-24 (helix 1) and 28-36 (helix 2). Oxidation of Met35 thus causes a local and selective disruption of helix 2. In addition to this helix-coil rearrangement in aqueous micelles, the CD data show that oxidation inhibits a coil-to-beta-sheet transition in water. These significant structural rearrangements in the C-terminal region of Abeta may be important clues to the chemistry and biology of Abeta(1-40) and Abeta(1-42).
Watson
A A
AA
Centre for Drug Design and Development, The University of Queensland, Brisbane.
Fairlie
D P
DP
Craik
D J
DJ
D000595:Amino Acid Sequence; D016229:Amyloid beta-Peptides / Q000737:chemistry* / Q000378:metabolism*; D002942:Circular Dichroism; D018360:Crystallography, X-Ray; D006801:Humans; D008715:Methionine / Q000378:metabolism*; D008823:Micelles; D008958:Models, Molecular; D008969:Molecular Sequence Data; D019906:Nuclear Magnetic Resonance, Biomolecular; D010084:Oxidation-Reduction; D010446:Peptide Fragments / Q000737:chemistry* / Q000378:metabolism*; D011487:Protein Conformation; D012996:Solutions; D014867:Water
D016229:Amyloid beta-Peptides; D008823:Micelles; D010446:Peptide Fragments; D012996:Solutions; C078592:amyloid beta-protein (1-40); D014867:Water; D008715:Methionine