pH-dependent structural transitions of Alzheimer amyloid peptides.
To understand the molecular interactions leading to the assembly of beta/44 protein into the hallmark fibrils of Alzheimer's disease (AD), we have examined the ability of synthetic peptides that correspond to the beta/A4 extracellular sequence to form fibrils over the range of pH 3-10. Peptides included the sequences 1-28, 19-28, 17-28, 15-28, 13-28, 11-28, and 9-28 of beta/A4. The model fibrils were compared with isolated amyloid with respect to morphology, conformation, tinctorial properties, and stability under denaturing conditions. Electron microscopy, Fourier-transform infrared (FT-IR) spectroscopy, and x-ray diffraction revealed that the ionization states of the amino acid sidechains appeared to be a crucial feature in fibril formation. This was reflected by the ability of several peptides to undergo fibril assembly and disassembly as a function of pH. Comparisons between different beta/A4 sequences demonstrated that the fibrillar structure representative of AD amyloid was dependent upon electrostatic interactions, likely involving His-13 and Asp-23, and hydrophobic interactions between uncharged sidechains contained within residues 17-21. The results also indicated an exclusively beta-sheet conformation for the synthetic (and possibly AD fibrils) in contrast to certain other (e.g., systemic) amyloids.
Fraser
P E
PE
Neurology Research, Children's Hospital, Boston, Massachusetts.
Nguyen
J T
JT
Surewicz
W K
WK
Kirschner
D A
DA
D000595:Amino Acid Sequence; D016229:Amyloid beta-Peptides / Q000737:chemistry* / Q000648:ultrastructure; D055592:Biophysical Phenomena; D001703:Biophysics; D001718:Birefringence; D003224:Congo Red; D006801:Humans; D006863:Hydrogen-Ion Concentration; D008854:Microscopy, Electron; D008969:Molecular Sequence Data; D015394:Molecular Structure; D011487:Protein Conformation; D013055:Spectrophotometry, Infrared; D014961:X-Ray Diffraction
D016229:Amyloid beta-Peptides; D003224:Congo Red