Conserved amyloid core structure of stop mutants of the human prion protein

Abstract

Prion diseases are associated with misfolding of the natively α-helical prion protein into isoforms that are rich in cross β-structure. However, both the mechanism by which pathological conformations are produced and their structural properties remain unclear. Using a combination of nuclear magnetic resonance spectroscopy, computation, hydroxyl radical probing combined with mass-spectrometry and site-directed mutagenesis, we showed that prion stop mutants that accumulate in amyloidogenic plaque-forming aggregates fold into a β-helix. The polymorphic residue 129 is located in the hydrophobic core of the β-helix in line with a critical role of the 129 region in the packing of protein chains into prion particles. Together with electron microscopy our data support a trimeric left-handed β-helix model in which the trimer interface is formed by residues L125, Y128 and L130. Different prion types or strains might be related to different aggregate structures or filament assemblies.

Keywords: :

• prion
• structure
• amyloid
• stop mutant
• trimer

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Disclosure of Potential Conflicts of Interest

No potential conflicts of interest were disclosed.

Acknowledgments

I thank Romina V. Hofele and Luis Fonseca for preparation of Figures 2C and 2D, respectively, and Dr Walter J. Schulz-Schäffer for fruitful discussions. This work was supported by the Cluster of Excellence and DFG Research Center “Nanoscale Microscopy and Molecular Physiology of the Brain.”