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Monomeric Aβ1–40 and Aβ1–42 Peptides in Solution Adopt Very Similar Ramachandran Map Distributions That Closely Resemble Random Coil
- Source :
- Biochemistry
- Publication Year :
- 2016
- Publisher :
- American Chemical Society, 2016.
-
Abstract
- The pathogenesis of Alzheimer's disease is characterized by the aggregation and fibrillation of amyloid peptides Aβ(1-40) and Aβ(1-42) into amyloid plaques. Despite strong potential therapeutic interest, the structural pathways associated with the conversion of monomeric Aβ peptides into oligomeric species remain largely unknown. In particular, the higher aggregation propensity and associated toxicity of Aβ(1-42) compared to that of Aβ(1-40) are poorly understood. To explore in detail the structural propensity of the monomeric Aβ(1-40) and Aβ(1-42) peptides in solution, we recorded a large set of nuclear magnetic resonance (NMR) parameters, including chemical shifts, nuclear Overhauser effects (NOEs), and J couplings. Systematic comparisons show that at neutral pH the Aβ(1-40) and Aβ(1-42) peptides populate almost indistinguishable coil-like conformations. Nuclear Overhauser effect spectra collected at very high resolution remove assignment ambiguities and show no long-range NOE contacts. Six sets of backbone J couplings ((3)JHNHα, (3)JC'C', (3)JC'Hα, (1)JHαCα, (2)JNCα, and (1)JNCα) recorded for Aβ(1-40) were used as input for the recently developed MERA Ramachandran map analysis, yielding residue-specific backbone ϕ/ψ torsion angle distributions that closely resemble random coil distributions, the absence of a significantly elevated propensity for β-conformations in the C-terminal region of the peptide, and a small but distinct propensity for αL at K28. Our results suggest that the self-association of Aβ peptides into toxic oligomers is not driven by elevated propensities of the monomeric species to adopt β-strand-like conformations. Instead, the accelerated disappearance of Aβ NMR signals in D2O over H2O, particularly pronounced for Aβ(1-42), suggests that intermolecular interactions between the hydrophobic regions of the peptide dominate the aggregation process.
- Subjects :
- 0301 basic medicine
Amyloid beta-Peptides
Magnetic Resonance Spectroscopy
Amyloid
Stereochemistry
Chemistry
Protein Conformation
Chemical shift
Nuclear Overhauser effect
Nuclear magnetic resonance spectroscopy
010402 general chemistry
01 natural sciences
Biochemistry
Random coil
Article
Peptide Fragments
0104 chemical sciences
Solutions
03 medical and health sciences
chemistry.chemical_compound
030104 developmental biology
Nuclear magnetic resonance
Protein structure
Monomer
Ramachandran plot
Subjects
Details
- Language :
- English
- ISSN :
- 15204995 and 00062960
- Volume :
- 55
- Issue :
- 5
- Database :
- OpenAIRE
- Journal :
- Biochemistry
- Accession number :
- edsair.doi.dedup.....973bc6597e2f698b394108e34ecb9b8f