Amyloid diseases of yeast: prions are proteins acting as genes

Abstract

The unusual genetic properties of the non-chromosomal genetic elements [URE3] and [PSI+] led to them being identified as prions (infectious proteins) of Ure2p and Sup35p respectively. Ure2p and Sup35p, and now several other proteins, can form amyloid, a linear ordered polymer of protein monomers, with a part of each molecule, the prion domain, forming the core of this β-sheet structure. Amyloid filaments passed to a new cell seed the conversion of the normal form of the protein into the same amyloid form. The cell's phenotype is affected, usually from the deficiency of the normal form of the protein. Solid-state NMR studies indicate that the yeast prion amyloids are in-register parallel β-sheet structures, in which each residue (e.g. Asn35) forms a row along the filament long axis. The favourable interactions possible for aligned identical hydrophilic and hydrophobic residues are believed to be the mechanism for propagation of amyloid conformation. Thus, just as DNA mediates inheritance by templating its own sequence, these proteins act as genes by templating their conformation. Distinct isolates of a given prion have different biological properties, presumably determined by differences between the amyloid structures. Many lines of evidence indicate that the Saccharomyces cerevisiae prions are pathological disease agents, although the example of the [Het-s] prion of Podospora anserina shows that a prion can have beneficial aspects.

Figure 1.

The in-register parallel architecture of yeast prion amyloid can explain templating of conformation. A. The unstructured prion domain of molecules newly joining the end of the amyloid filament are directed to assume the same conformation as molecules already in the filament by the favorable interactions between identical side chains that can only occur if the molecules are in-register [77]. B. Three interactions of an amino acid residue are shown. The black lines show the main chain hydrogen bonds of the β-sheet. The black double-headed arrow indicates the intermolecular side-chain interactions between identical residues (emphasized in A). Also shown are the interactions between non-identical side chains in the plane perpendicular to the long axis of the filaments. These interactions have been studied by X-ray crystallography of short peptides [78].