C-Terminal Turn Stability Determines Assembly Differences between Aβ40 and Aβ42

• Published in: Journal of molecular biology Vol. 425; no. 2; pp. 292 - 308
• Main Authors: Roychaudhuri, Robin, Yang, Mingfeng, Deshpande, Atul, Cole, Gregory M., Frautschy, Sally, Lomakin, Aleksey, Benedek, George B., Teplow, David B.
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 23-01-2013
• Subjects: Alzheimer disease; Alzheimer's disease; amino acids; amyloid; Amyloid beta-Peptides - chemistry; Amyloid beta-Peptides - pharmacology; amyloid β-protein; Animals; Cell Survival - drug effects; Cerebral Cortex - cytology; Cerebral Cortex - drug effects; Hippocampus - cytology; Hippocampus - drug effects; Hydrogen Bonding; Hydrophobic and Hydrophilic Interactions; hydrophobic bonding; Models, Molecular; Molecular Dynamics Simulation; Neurons - cytology; Neurons - drug effects; Peptide Fragments - chemistry; Peptide Fragments - pharmacology; peptides; Protein Structure, Secondary; Rats; Structure-Activity Relationship; toxicity; β-hairpin; ThT; RT; AD; EM; amyloid β-protein; DLS; PICUP; REMD; MTS; SC; Aβ; LDH; LMW; β-hairpin; Alzheimer's disease
• ISSN: 0022-2836; 1089-8638
• DOI: 10.1016/j.jmb.2012.11.006

Oligomerization of the amyloid β-protein (Aβ) is a seminal event in Alzheimer's disease. Aβ42, which is only two amino acids longer than Aβ40, is particularly pathogenic. Why this is so has not been elucidated fully. We report here results of computational and experimental studies revealing a C-terminal turn at Val36–Gly37 in Aβ42 that is not present in Aβ40. The dihedral angles of residues 36 and 37 in an Ile31–Ala42 peptide were consistent with β-turns, and a β-hairpin-like structure was indeed observed that was stabilized by hydrogen bonds and by hydrophobic interactions between residues 31–35 and residues 38–42. In contrast, Aβ(31–40) mainly existed as a statistical coil. To study the system experimentally, we chemically synthesized Aβ peptides containing amino acid substitutions designed to stabilize or destabilize the hairpin. The triple substitution Gly33Val–Val36Pro–Gly38Val (“VPV”) facilitated Aβ42 hexamer and nonamer formation, while inhibiting formation of classical amyloid-type fibrils. These assemblies were as toxic as were assemblies from wild-type Aβ42. When substituted into Aβ40, the VPV substitution caused the peptide to oligomerize similarly to Aβ42. The modified Aβ40 was significantly more toxic than Aβ40. The double substitution d-Pro36–l-Pro37 abolished hexamer and dodecamer formation by Aβ42 and produced an oligomer size distribution similar to that of Aβ40. Our data suggest that the Val36–Gly37 turn could be the sine qua non of Aβ42. If true, this structure would be an exceptionally important therapeutic target.
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► A structural basis for the enhanced amyloidogenicity of Aβ42 has been determined. ► A β-turn exists at the C-terminus of Aβ42 but not Aβ40. ► Amino acid substitutions within the turn can interconvert Aβ40 and Aβ42. ► The turn could be a useful therapeutic target.