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Proc Natl Acad Sci U S A. 2005 Nov 1;102(44):15871-6. Epub 2005 Oct 24.

Molecular-level secondary structure, polymorphism, and dynamics of full-length alpha-synuclein fibrils studied by solid-state NMR.

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  • 1Department of NMR-Based Structural Biology, Max Planck Institute for Biophysical Chemistry, 37077 Göttingen, Germany. hehe@nmr.mpibpc.mpg.de

Abstract

The 140-residue protein alpha-synuclein (AS) is able to form amyloid fibrils and as such is the main component of protein inclusions involved in Parkinson's disease. We have investigated the structure and dynamics of full-length AS fibrils by high-resolution solid-state NMR spectroscopy. Homonuclear and heteronuclear 2D and 3D spectra of fibrils grown from uniformly (13)C/(15)N-labeled AS and AS reverse-labeled for two of the most abundant amino acids, K and V, were analyzed. (13)C and (15)N signals exhibited linewidths of <0.7 ppm. Sequential assignments were obtained for 48 residues in the hydrophobic core region. We identified two different types of fibrils displaying chemical-shift differences of up to 13 ppm in the (15)N dimension and up to 5 ppm for backbone and side-chain (13)C chemical shifts. EM studies suggested that molecular structure is correlated with fibril morphology. Investigation of the secondary structure revealed that most amino acids of the core region belong to beta-strands with similar torsion angles in both conformations. Selection of regions with different mobility indicated the existence of monomers in the sample and allowed the identification of mobile segments of the protein within the fibril in the presence of monomeric protein. At least 35 C-terminal residues were mobile and lacked a defined secondary structure, whereas the N terminus was rigid starting from residue 22. Our findings agree well with the overall picture obtained with other methods and provide insight into the amyloid fibril structure and dynamics with residue-specific resolution.

PMID:
16247008
PMCID:
PMC1276071
DOI:
10.1073/pnas.0506109102
[PubMed - indexed for MEDLINE]
Free PMC Article
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