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Structural studies of amyloid fibrils by solid-state NMR

Amyloids are fibrillar protein aggregates that are a pathological hallmark of a series of prevalent neurodegenerative diseases such as Alzheimers’s and Parkinson’s disease. It is therefore of great interest to understand the process of amyloid formation on a molecular level. A subset of amyloids can replicate by seeded nucleation and propagate as prions, infectious agents composed solely of protein. Structurally, the polypeptide chain of amyloids has folded into a cross-β structure with β-sheets running perpendicularly to the long axis of the fibril. Amyloids do not crystallize, are mostly insoluble and thus do not constitute a promising target for the standard techniques in structural biology, X-ray crystallography and solution-state nuclear magnetic resonance spectroscopy (NMR). In the past decade, amyloids have been extensively studied by solid-state NMR spectroscopy, a method by which proteins can be investigated even if they are in a a solid yet non-crystalline state. Sequential resonance assignment of protein spectra, which is the correlation of each observed NMR frequency with a nuclear spin of an amino acid in the primary sequence, is a prerequisite for all high-resolution NMR studies. Using the globular domain of the fungal HET-s prion from Podospora anserina as a model system, we evaluated a set of three-dimensional correlation experiments for this purpose. Our concept has since been applied to several de novo assignments, among them a prion protein of more than 350 residues. The mammalian prion protein PrP in its infectious form is linked to bovine spongiform encephalopathy (BSE) in cattle and a variant of Creutzfeldt-Jakob disease (CJD) in humans. Prion proteins have also been discovered in filamentous fungi and yeast organisms and are frequently used in biophysics and cell biology as model systems to study prion structure, propagation and infectious properties. The Sup35 protein from baker’s yeast (Saccharomyces cerevisiae) serves as such a model of prion behavior in vivo and in vitro. Since Sup35p contains almost 700 amino acid residues, it is often reduced to conveniently small fragments that are better accessible by biophysical techniques. Our results challenge the assumption that such small constructs can faithfully represent the entire structural complexity of the full-length prion. Based on the sequential resonance assignment of the amyloid core of both the full-length prion protein and a commonly used fragment