Untangling the structure of fibrils

Amyloid fibrils, those tangled protein filaments that are a hallmark of many disorders including Alzheimer’s, Parkinson’s, and prion diseases, are posing a phenomenal challenge to structural studies, as they cannot be crystallised and are too large for conventional NMR structure elucidation. Pushing the limits of alternative methods, researchers have obtained structural models of amyloid fibrils using x-ray diffraction and cryo-electron microscopy. A Swiss team has now added solid state NMR to the range of methods that can reveal details of amyloid structure.

Beat Meier and colleagues at the Swiss Federal Institute of Technology in Zurich studied a protein called HET-s, which is involved in a specific kind of programmed cell death (heterokaryon incompatibility). HET-s acts as a prion protein in that it can convert between two different conformations, only one of which forms amyloid fibrils in the living organism. Meier’s team prepared a fragment of this form of the protein, which contains the residues that appear to form the core of the amyloid fibrils found in vivo, and residues responsible for the conformational switch.

Studying amyloid fibrils of this fragment by solid state NMR, the researchers obtained much better resolved cross peaks suitable for structure determination.¹ Such data have so far only been available for one other amyloid (but non-prion) fibril, formed from a transthyretin fragment.²

Preliminary analysis of the data suggests that roughly two thirds of the 72-residue protein fragment are highly ordered in the amyloid fibril, whereas the remaining third, which can be pinned down precisely to certain parts of the molecule, is highly disordered.

’It is a very nice work in progress,’ say Chris Dobson, professor of chemistry at the University of Cambridge, UK. It adds to earlier studies, he says, by showing that NMR undoubtedly has a major role to play in structural studies of the amyloid phenomenon in general. ’We can expect continuing progress from a range of groups around the world.’

Michael Gross