OL-01: Implications of the folded in-register parallel b-sheet structure of infectious prion amyloids
Reed B. Wickner
National Institutes of Health/National Institutes of Diabetes and Digestive and Kidney Diseases/Laboratory of Biochemistry and Genetics, Bethesda, MD, USA
The yeast prions [URE3], [PSI+] and [PIN+] are amyloids of Ure2p, Sup35p and Rnq1p, respectively. Like mammalian prions, these yeast prions have several conformationally distinct amyloid forms (strains/variants) with different properties. How a single protein sequence can be the basis of an array of prions, each stably self-propagating is the central puzzle of the prion phenomenon.
We showed that infectious amyloids of the prion domains of Ure2p, Sup35p and Rnq1p are each folded in-register parallel β-sheets. Each residue of the protein is aligned with the same residue of the other molecules of the filament, with, for example, a line of Gln35 residues stretching the length of the filament. This in-register alignment is enforced by favorable side chain - side chain interactions between identical residues. Aligned Gln, Asn, Ser, or Thr residues form a chain of hydrogen bonds extending the length of the filament. Aligned hydrophobic residues form a chain of hydrophobic interactions. These prion domains have few charged residues whose interaction would be unfavorable. This folded in-register parallel β-sheet amyloid architecture naturally suggests a mechanism by which a specific amyloid structure can be faithfully propagated, with the protein molecules in the filament templating their conformation. We propose that prion variants/strains differ in the location of the folds in the sheets, equivalent to the locations of the turns in the β-strands. In order for a molecule joining the end of a filament to enjoy the favorable interactions of identical side chains that stabilize the in-register parallel structure, it must bend its peptide chain in the same locations as do the molecules already in the filament. This results in the new molecule acquiring the same conformation as the molecules already in the filament, a conformational templating analogous to the sequence templating by DNA. Thus, a prion can act as a non-chromosomal gene in yeast, or maintain its special disease features in mammals (incubation time, brain regions most affected) or in yeast (degree of pathogenicity). The architecture of highly infectious PrPSc remains in doubt, but many human amyloidoses showing prion-like features are based on amyloids with the same folded in-register β-sheet architecture as we have documented for the highly infectious yeast prion amyloids.
We will also summarize studies on anti-prion systems in yeast determined by the Btn2 and Cur1 proteins.