Final Activity Report Summary - SSNMR-Amyloids (Amyloid fibril structures explored by solid-state NMR.)
Prions and amyloid fibrils are associated with several animal and human diseases. Despite the paramount importance of the structural aspects, no atomic resolution structure of a prion in its fibrillar state had been reported. Solid-state NMR is to date the only technique capable of obtaining the structure of such non-crystalline and non-soluble compounds. We have obtained the structure of amyloid fibrils produced in vitro from the prion-forming domain (residues 218-289) of the HET-s prion from the filamentous fungus Podospora anserina using solid-state NMR techniques.
These results give a structural explanation of the stability of the amyloid fibrils. The HET-s(218-289) prion forms a left-handed beta-solenoid, of which each molecule represents two helical windings. This beta-solenoid is stabilized not only by the H-bond network formed by the parallel stacking of the beta-strands, but also by three salt-bridges, two asparagine-ladders, and the presence of a solvent-protected rigid triangular hydrophobic core. Furthermore, an improved protocol for structure determination of amyloid fibrils using solid-state NMR techniques is proposed on this example.
These results give a structural explanation of the stability of the amyloid fibrils. The HET-s(218-289) prion forms a left-handed beta-solenoid, of which each molecule represents two helical windings. This beta-solenoid is stabilized not only by the H-bond network formed by the parallel stacking of the beta-strands, but also by three salt-bridges, two asparagine-ladders, and the presence of a solvent-protected rigid triangular hydrophobic core. Furthermore, an improved protocol for structure determination of amyloid fibrils using solid-state NMR techniques is proposed on this example.