PRION FUNCTION AND DYSFUNCTION - A STRUCTURE-BASED SCENARIO

Prion diseases are transmissible, neurodegenerative disorders associat ed with as yet incompletely defined isoforms of a cellular protein ter med prion protein (PrP). We have now identified in PrP structural info rmation compatible with nucleotide- and nucleic acid-binding. As such, PrP contains a putative nicotinamide adenine dinucleotide (NADH)-bind ing site. Moreover, the PrP octarepeats reveal homology to the nucleic acid-binding and strand-annealing octarepeats of mammalian heterogene ous ribonucleoprotein (RNP) A1. Therefore, PrP may have NADH-dependent oxidoreductase activity as well as A1-like functions such as nucleic acid annealing and splicing. Moreover, we propose that infectious prio ns are propagated through a dynamic molecular symbiosis between a ribo zyme-like nucleic acid and a conformational isomer of the RNP-like pri on protein. Thus, our model has important implications for the underst anding and treatment of prion diseases.