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Kinetic profile of amyloid formation in the presence of an aromatic inhibitor by nuclear magnetic resonance.

ABSTRACT: The self-assembly of amyloid proteins into ?-sheet rich assemblies is associated with human amyloidoses including Alzheimer's disease, Parkinson's disease, and type 2 diabetes. An attractive therapeutic strategy therefore is to develop small molecules that would inhibit protein self-assembly. Natural polyphenols are potential inhibitors of ?-sheet formation. How these compounds affect the kinetics of self-assembly studied by thioflavin T (ThT) fluorescence is not understood primarily because their presence interferes with ThT fluorescence. Here, we show that by plotting peak intensities from nuclear magnetic resonance (NMR) against incubation time, kinetic profiles in the presence of the polyphenol can be obtained from which kinetic parameters of self-assembly can be easily determined. In applying this technique to the self-assembly of the islet amyloid polypeptide in the presence of curcumin, a biphenolic compound found in turmeric, we show that the kinetic profile is atypical in that it shows a prenucleation period during which there is no observable decrease in NMR peak intensities.

SUBMITTER: Liu G

PROVIDER: S-EPMC4025671 | biostudies-literature | 2012 Oct

REPOSITORIES: biostudies-literature

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Kinetic profile of amyloid formation in the presence of an aromatic inhibitor by nuclear magnetic resonance.

Liu Gai G Gaines Jennifer C JC Robbins Kevin J KJ Lazo Noel D ND

ACS medicinal chemistry letters 20120828 10

The self-assembly of amyloid proteins into β-sheet rich assemblies is associated with human amyloidoses including Alzheimer's disease, Parkinson's disease, and type 2 diabetes. An attractive therapeutic strategy therefore is to develop small molecules that would inhibit protein self-assembly. Natural polyphenols are potential inhibitors of β-sheet formation. How these compounds affect the kinetics of self-assembly studied by thioflavin T (ThT) fluorescence is not understood primarily because the ...[more]

PMID: 24900390

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Project description:The microtubule-associated protein tau aggregates into distinct neurofibrillary tangles in brains afflicted with multiple neurodegenerative diseases such as Alzheimer's disease and corticobasal degeneration (CBD). The mechanism of tau misfolding and aggregation is poorly understood. Determining the structure, dynamics, and water accessibility of tau filaments may provide insight into the pathway of tau misfolding. Here, we investigate the hydration and dynamics of the β-sheet core of heparin-fibrillized 0N4R tau using solid-state nuclear magnetic resonance spectroscopy. This β-sheet core consists of the second and third microtubule-binding repeats, R2 and R3, respectively, which form a hairpin. Water-edited two-dimensional (2D) 13C-13C and 15N-13C correlation spectra show that most residues in R2 and R3 domains have low water accessibility, indicating that this hairpin is surrounded by other proteinaceous segments. However, a small number of residues, especially S285 and S316, are well hydrated compared to other Ser and Thr residues, suggesting that there is a small water channel in the middle of the hairpin. To probe whether water accessibility correlates with protein dynamics, we measured the backbone N-H dipolar couplings of the β-sheet core. Interestingly, residues in the fourth microtubule-binding repeat, R4, show rigid-limit N-H dipolar couplings, even though this domain exhibits weaker intensities in the 2D 15N-13C correlation spectra. These results suggest that the R4 domain participates in cross-β hydrogen bonding in some of the subunits but exhibits dynamic disorder in other subunits. Taken together, these hydration and dynamics data indicate that the R2-R3 hairpin of 0N4R tau is shielded from water by other proteinaceous segments on the exterior but contains a small water pore in the interior. This structural topology has various similarities with the CBD tau fibril structure but also shows specific differences. The disorder of the R4 domain and the presence of a small water channel in the heparin-fibrillized 4R tau have implications for the structure of tau fibrils in diseased brains.

Dataset Information

Kinetic profile of amyloid formation in the presence of an aromatic inhibitor by nuclear magnetic resonance.

Publications

Kinetic profile of amyloid formation in the presence of an aromatic inhibitor by nuclear magnetic resonance.

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