Structural Biology of Prion Protein

Structural Biology of Prion Protein
 

One of the strongest arguments supporting the "protein-only hypothesis" is the link between prion diseases and inherited human (Hu) mutations in the PRNP gene. Several point mutations leading to familial Creutzfeldt-Jakob disease, Gerstmann-Sträussler-Scheinker (GSS) disease, fatal familial insomnia have been identified. Our understanding of the mechanisms by which mutations cause disease remains limited. We believe that high-resolution 3D structures of the mutated PrP, more susceptible for spontaneous conversion into the pathogenic form, will help us to understand the molecular mechanism at early stages of the disease. Recently, we determined the NMR structures of the truncated recombinant HuPrP containing the GSS-related Q212P mutation and the pathological V210I mutation linked to genetic Creutzfeldt-Jakob disease. These structures revealed unique conformational features compared to the known structures of other mammalian PrP. The most remarkable differences involve the C-terminal end of the protein and the loop region.

To provide new information on the role of pathological point mutations on PrP structure, we are now investigating the high-resolution 3D structures of different disease-linked HuPrP mutants. These investigations offer new clues about the earliest events of the pathogenic conversion process that could be used for the development of antiprion drugs.

written by Gabriele Giachin This e-mail address is being protected from spambots. You need JavaScript enabled to view it. and Giuseppe Legname This e-mail address is being protected from spambots. You need JavaScript enabled to view it.