Solution structures of micelle-bound amyloid beta-(1-40) and beta-(1-42) peptides of Alzheimer's disease.
The amyloid beta-peptide is the major protein constituent of neuritic plaques in Alzheimer's disease. The beta-peptide varies slightly in length and exists in two predominant forms: (1) the shorter, 40 residue beta-(1-40), found mainly in cerebrovascular amyloid; and (2) the longer, 42 residue beta-(1-42), which is the major component in amyloid plaque core deposits. We report here that the sodium dodecyl sulphate (SDS) micelle, a membrane-mimicking system for biophysical studies, prevents aggregation of the beta-(1-40) and the beta-(1-42) into the neurotoxic amyloid-like, beta-pleated sheet structure, and instead encourages folding into predominantly alpha-helical structures at pH 7.2. Analysis of the nuclear Overhauser enhancement (NOE) and the alphaH NMR chemical shift data revealed no significant structural differences between the beta-(1-40) and the beta-(1-42). The NMR-derived, three-dimensional structure of the beta-(1-42) consists of an extended chain (Asp1-Gly9), two alpha-helices (Tyr10-Val24 and Lys28-Ala42), and a looped region (Gly25-Ser26-Asn27). The most stable alpha-helical regions reside at Gln15-Val24 and Lys28-Val36. The majority of the amide (NH) temperature coefficients were less than 5, indicative of predominately strong NH backbone bonding. The lack of a persistent region with consistently low NH coefficients, together with the rapid NH exchange rates in deuterated water and spin-labeled studies, suggests that the beta-peptide is located at the lipid-water interface of the micelle and does not become inbedded within the hydrophobic interior. This result has implications for the circulation of membrane-bound beta-peptide in biological fluids, and may also facilitate the design of amyloid inhibitors to prevent an alpha-helix-->beta-sheet conversion in Alzheimer's disease.
Shao
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Department of Chemistry, Case Western Reserve University, Cleveland, OH, 44106, USA.
Jao
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Zagorski
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D000544:Alzheimer Disease; D000595:Amino Acid Sequence; D016229:Amyloid beta-Peptides / Q000737:chemistry*; D006801:Humans; D006859:Hydrogen; D008823:Micelles; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000737:chemistry*; D010455:Peptides / Q000737:chemistry*; D017433:Protein Structure, Secondary; D012996:Solutions; D013113:Spin Labels; D013696:Temperature
D016229:Amyloid beta-Peptides; D008823:Micelles; D010446:Peptide Fragments; D010455:Peptides; D012996:Solutions; D013113:Spin Labels; C078592:amyloid beta-protein (1-40); C075222:amyloid beta-protein (1-42); D006859:Hydrogen