Dataset Information

C-terminal turn stability determines assembly differences between A?40 and A?42.

ABSTRACT: Oligomerization of the amyloid ?-protein (A?) is a seminal event in Alzheimer's disease. A?42, which is only two amino acids longer than A?40, 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 A?42 that is not present in A?40. The dihedral angles of residues 36 and 37 in an Ile31-Ala42 peptide were consistent with ?-turns, and a ?-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, A?(31-40) mainly existed as a statistical coil. To study the system experimentally, we chemically synthesized A? peptides containing amino acid substitutions designed to stabilize or destabilize the hairpin. The triple substitution Gly33Val-Val36Pro-Gly38Val ("VPV") facilitated A?42 hexamer and nonamer formation, while inhibiting formation of classical amyloid-type fibrils. These assemblies were as toxic as were assemblies from wild-type A?42. When substituted into A?40, the VPV substitution caused the peptide to oligomerize similarly to A?42. The modified A?40 was significantly more toxic than A?40. The double substitution d-Pro36-l-Pro37 abolished hexamer and dodecamer formation by A?42 and produced an oligomer size distribution similar to that of A?40. Our data suggest that the Val36-Gly37 turn could be the sine qua non of A?42. If true, this structure would be an exceptionally important therapeutic target.

SUBMITTER: Roychaudhuri R

PROVIDER: S-EPMC3540122 | biostudies-literature | 2013 Jan

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

C-terminal turn stability determines assembly differences between Aβ40 and Aβ42.

Roychaudhuri Robin R Yang Mingfeng M Deshpande Atul A Cole Gregory M GM Frautschy Sally S Lomakin Aleksey A Benedek George B GB Teplow David B DB

Journal of molecular biology 20121112 2

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 indee ...[more]

PMID: 23154165

Similar Datasets

Project description:BACKGROUND: DrTx(1-42) (a carboxyl-terminally truncated version of drosotoxin) is a potent and selective blocker of tetrodotoxin-resistant (TTX-R) Na(+) channels in rat dorsal root ganglion neurons with analgesic activity. This purpose is to identify key amino acids which are responsible for both blocking and analgesic effects of DrTx(1-42). METHODS: On the basis of previous study, we designed five mutants of DrTx(1-42) (delN, D8A, D8K, G9A, and G9R) in the amino-terminal turn (N-turn) region, a proposed functional region located in the amino-terminus of the molecule. All these mutants were expressed in E.coli and purified by RP-HPLC. Electrophysiological properties of these analogues were examined by whole-cell patch-clamp recordings and their antinociceptive effects were investigated by the formalin test and acetic acid induced writhing test. RESULTS: All the mutants except for G9A possess a similar secondary structure to that of DrTx(1-42), as identified by circular dichroism analysis. Three mutants (delN, D8A and G9A) were found almost inactive to TTX-R Na(+) channels, whereas D8K retains similar activity and G9R showed decreased potency when compared with the wild-type molecule. Consistent with the electrophysiological observations, D8K and G9R exhibited antinociceptive effects in the second phase (inflammatory pain) of the formalin test and the acetic acid induced writhing test, while delN, D8A and G9A lack such effects. CONCLUSIONS: Our results show that the N-turn is closely related to function of DrTx(1-42). The mutant (D8A) as a control peptide further reveals that a charged residue at site 8 of the N-terminus is important for channel blockade and analgesic activity. This study indicates that blocking of voltage-gated TTX-R Na(+) channel in DRG neurons contributes to analgesic effect in rat inflammatory pain. Structural and functional data described here offers support for the development of novel analgesic drugs through targeting TTX-R Na(+) channels.

Dataset Information

C-terminal turn stability determines assembly differences between A?40 and A?42.

Publications

C-terminal turn stability determines assembly differences between Aβ40 and Aβ42.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure