Discrete conformational changes as regulators of the hydrolytic properties of beta-amyloid (1-40).
Beta-amyloid (1-40) (Abeta), the main component of senile plaques seen in the brains of Alzheimer's disease patients, was found to be toxic both as fibrils and smaller soluble globular aggregates. The hydrolytic properties of Abeta, a new biochemical activity described previously [Brzyska M, Bacia A & Elbaum D (2001) Eur J Biochem 268, 3443-3454], may contribute to its overall toxicity. In this study, the hydrolysis of fluorescein ester series was studied under predetermined conditions affecting Abeta hydrophobicity and conformation. Reaction products of the most effectively decomposed ester (dibutyrate) were characterized using HPLC and ESI-MS. Hydrophobicity of Abeta, as measured by bis-8-anilinonaphthalene fluorescence, correlated with its hydrolytic abilities. FTIR and CD data analysis showed a relationship between enhanced hydrolytic abilities and Abeta structure. Seriously limited hydrolysis caused by higher peptide concentrations is consistent with monomeric/dimeric Abeta species participation in the process, confirmed by thioflavine T binding. Inhibition of hydrolysis was caused by beta-sheet breaker peptide (LPFFD), indicating that the Abeta central hydrophobic cluster (amino acids 17-21) participates in the process. The reported Abeta properties suggest that small conformational alterations of the peptide structure may have a pronounced effect on its functions and biological activity.
Brzyska
Maria
M
Laboratory of Bio-Physical Methods, Nencki Institute of Experimental Biology, Polish Academy of Sciences, Warsaw, Poland. M.Brzyska@nencki.gov.pl
Trzesniewska
Katarzyna
K
Gers
Tomasz
T
Elbaum
Danek
D
D000595:Amino Acid Sequence; D016229:Amyloid beta-Peptides / Q000737:chemistry*; D002942:Circular Dichroism; D005452:Fluoresceins / Q000737:chemistry; D005456:Fluorescent Dyes / Q000737:chemistry; D006801:Humans; D006868:Hydrolysis; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000737:chemistry*; D011487:Protein Conformation; D017550:Spectroscopy, Fourier Transform Infrared
D016229:Amyloid beta-Peptides; D005452:Fluoresceins; D005456:Fluorescent Dyes; D010446:Peptide Fragments; C078592:amyloid beta-protein (1-40)