Solution Structures of β Peptide and Its Constituent Fragments: Relation to Amyloid Deposition

Abstract

The secondary structures in solution of the synthetic, naturally occurring, amyloid beta peptides, residues 1 to 42 [beta (1-42)] and beta (1-39), and related fragments, beta (1-28) and beta (29-42), have been studied by circular dichroism and two-dimensional nuclear magnetic resonance spectroscopy. In patients with Alzheimer's disease, extracellular amyloid plaque core is primarily composed of beta (1-42), whereas cerebrovascular amyloid contains the more soluble beta (1-39). In aqueous trifluoroethanol solution, the beta (1-28), beta (1-39), and beta (1-42) peptides adopt monomeric alpha-helical structures at both low and high pH, whereas at intermediate pH (4 to 7) an oligomeric beta structure (the probable structure in plaques) predominates. Thus, beta peptide is not by itself an insoluble protein (as originally thought), and localized or normal age-related alterations of pH may be necessary for the self-assembly and deposition of beta peptide. The hydrophobic carboxyl-terminal segment, beta(29-42), exists exclusively as an oligomeric beta sheet in solution, regardless of differences in solvent, pH, or temperature, suggesting that this segment directs the folding of the complete beta (1-42) peptide to produce the beta-pleated sheet found in amyloid plaques.

Structures and Free Energy Landscapes of the Wild-Type and A30P Mutant-Type α-Synuclein Proteins with Dynamics

“…The helical and β-sheet structure formations have been proposed to play crucial roles in the aggregation process of intrinsically disordered fibrillogenic proteins at the center of neurodegenerative diseases. 12,14,24,41 Within the N-terminal region (Met1-Lys60) of the wild-type and A30P mutant-type αS, we detect abundant α-helix formation at Ala19-Lys23 and 3 10 -helix formation at Val15-Ala18, Glu20-Thr22, Gly41-Thr44, and Thr54-Lys60 varying between 20% and 35% ( Figure 1). Interestingly, Gly7-Glu13, Val15-Ala17, Lys32-Val40, and Lys43-Gly47 adopt more prominent helical structure (α-helix or 3 10 -helix; up to 30%) in the structures of the A30P mutanttype than in those of the wild-type αS protein.…”

Nicotine Inhibits Amyloid Formation by the β-Peptide

“…Although the reasons for these deviations are unknown, they are believed to arise in part from differences in the aggregation states and the solution structures of the -peptides. The ability to produce the presumably neurotoxic, aggregated -sheet structure is dependent on many factors, particularly the peptide concentration, ionic strength, and solvent polarity (Barrow & Zagorski, 1991;Barrow et al, 1992;Hilbich et al, 1991;Shen et al, 1994;Snyder et al, 1994). For example, the aggregation rate is extremely rapid in aqueous acetonitrile solutions, such as those used for HPLC purification of the peptide (Shen & Murphy, 1995).…”

“…The -(1-42) concentration was now 50 µM. Because the aggregational properties of the peptide rapidly increase below pH 7 (Fraser et al, 1991;Barrow & Zagorski, 1991;Burdick et al, 1992), the pH of the final solution was always immediately checked to ensure that it was above 7.1. In most cases, the pH remained at 7.2, indicating that a 14 mM phosphate buffer concentration was adequate to maintain the pH.…”

“…The -peptide is a normal, soluble physiological component (Gravina et al, 1995). However, under certain environmental conditions, the -peptide can produce oligomeric -sheet structures that eventually precipitate as amyloid plaques (Kirschner et al, 1987;Gorévic et al, 1987;Hilbich et al, 1991;Barrow & Zagorski, 1991;Burdick et al, 1992;Terzi et al, 1994). The soluble -sheet structure has the following properties that are relevant to amyloidosis in AD: (1) it is a precursor to the insoluble -pleated sheet structure in amyloid plaque, (2) it can act as a seed that nucleates amyloid formation Snyder et al, 1994), and (3) it is neurotoxic to hippocampal neuronal cultures (Simmons et al, 1994;Harrigan et al, 1995;Pike et al, 1995).…”

Identification of structural variations in the carboxyl terminus of Alzheimer's disease-associated βA4[1–42] amyloid using a monoclonal antibody

“…This structure is modified with increasing temperature and pH so that at pH 1±4 or above 7 the peptides adopt a random coil structure but aggregate in a b-sheet conformation between pH 4 and 7. In contrast, the region 0 1 2 encompassing bA4[29±42] has been shown to adopt a b-strand conformation regardless of temperature and pH, and as such has been reported to direct the protein folding of the entire bA4 sequence to produce the b-pleated sheet structure found in amyloid deposits [7,8,15,16] In light of these observations, this study has demonstrated a unique C-terminal conformation within bA4[1±42], as defined using MoAb 3B9 which binds the GVV epitope. These results support the hypothesis that key residues within the C-terminal region of bA4[1±42] generate a unique peptide conformation which may be responsible for initiating the bA4 polymerization and amyloid fibril formation observed in the neuritic and diffuse plaques of AD.…”