La protéine prion: Structure, dynamique et conversion in vitro

Abstract

The prion hypothesis of S.B. Prusiner has challenged not only the molecular biology but also the main paradigms of structural biology. Indeed, the prion hypothesis supposes that : 1) a protein can adopt two different conformations and 2) that the rogue isoform can convert the normal isoform to its own structure. We review the present knowledge on the spatial structure and folding characteristics of the prion protein. Atomic structure of the recombinant prion protein has been solved by NMR. It is constituted of a core mainly under α-helix conformation and a long unstructured N-terminal. This spatial structure does not reveal specific any features that would simply explain the existence of the two structures. The folding studies show a very simple pathway when operated under neutral pH, however at acidic pH the protein can adopt a β-sheeted secondary structure that results in amyloïd formation, unfortunately this form is not infectious. It is known that in vivo, chaperones assist protein folding. Many experimental results suggest the participation of chaperones to the prion genesis, but we still can neither produce infectious protein nor understand how these chaperones could participate to the phenomenon. In vitro conversion of the normal isoforme to a proteinase K resistant protein has been successfully designed, but has not yet produced an infectious protein. Altogether, the experimental results do not discount the structural aspects of the prion hypothesis but have failed to confirm it. Some new working hypotheses are being still examined by researchers.