pH-dependent structural transitions of Alzheimer amyloid peptides

• Published in: Biophysical journal Vol. 60; no. 5; pp. 1190 - 1201
• Main Authors: Fraser, P.E., Nguyen, J.T., Surewicz, W.K., Kirschner, D.A.
• Format: Journal Article
• Language: English
• Published: Bethesda, MD Elsevier Inc 01.11.1991; Biophysical Society
• Subjects: Alzheimer's disease; Amino Acid Sequence; Amyloid beta-Peptides - chemistry; Amyloid beta-Peptides - ultrastructure; Analytical, structural and metabolic biochemistry; beta -amyloid protein; Biological and medical sciences; Biophysical Phenomena; Biophysics; Birefringence; Congo Red; effects on; Fundamental and applied biological sciences. Psychology; Humans; Hydrogen-Ion Concentration; man; Microscopy, Electron; Miscellaneous; Molecular Sequence Data; Molecular Structure; Protein Conformation; Proteins; Spectrophotometry, Infrared; structure; X-Ray Diffraction; Infrared spectrometry; Alzheimer disease; Morphology; Dyeability; pH; Amyloid; Fibrillar structure; Electron microscopy; β-Structure; X ray diffraction; Conformation; Fibril
• ISSN: 0006-3495; 1542-0086
• DOI: 10.1016/S0006-3495(91)82154-3

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.