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Journal Article

Burial of the polymorphic residue 129 in amyloid fibrils of prion stop mutants.

MPS-Authors
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Skora,  L.
Research Group of Protein Structure Determination using NMR, MPI for biophysical chemistry, Max Planck Society;

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Fonseca,  L.
Research Group of Protein Structure Determination using NMR, MPI for biophysical chemistry, Max Planck Society;

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Riedel,  D.
Facility for Electron Microscopy, MPI for biophysical chemistry, Max Planck Society;

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Giller,  K.
Department of NMR-Based Structural Biology, MPI for biophysical chemistry, Max Planck Society;

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Becker,  S.
Department of NMR-Based Structural Biology, MPI for biophysical chemistry, Max Planck Society;

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Zweckstetter,  M.
Research Group of Protein Structure Determination using NMR, MPI for biophysical chemistry, Max Planck Society;

Fulltext (public)

1586811.pdf
(Publisher version), 3MB

Supplementary Material (public)

1586811-Suppl.pdf
(Supplementary material), 219KB

Citation

Skora, L., Fonseca, L., Hofele, R. V., Riedel, D., Giller, K., Watzlawik, J., et al. (2013). Burial of the polymorphic residue 129 in amyloid fibrils of prion stop mutants. Journal of Biological Chemistry, 288(5), 2994-3002. doi:10.1074/jbc.M112.423715 jbc.M112.423715.


Cite as: http://hdl.handle.net/11858/00-001M-0000-0010-8FBF-7
Abstract
Misfolding of the natively alpha-helical prion protein into a beta-sheet rich isoform is related to various human diseases such as Creutzfeldt-Jakob disease and Gerstmann-Straeussler-Scheinker-like syndrome. In humans the disease phenotype is modified by a methionine/valine polymorphism at codon 129 of the prion protein gene. Using a combination of H/D exchange coupled to NMR spectroscopy, hydroxyl radical probing detected by mass spectrometry and site-directed mutagenesis we demonstrate that stop mutants of the human prion protein have a conserved amyloid core. The 129 residue is deeply buried in the amyloid core structure and its mutation strongly impacts aggregation. Taken together the data support a critical role of the polymorphic residue 129 of the human prion protein in aggregation and disease.