Prion proteins in signal transduction

Abstract

A prion protein is essentially a protein that can replicate itself. The mechanism of propagation is characterized by the ability of the protein in the prion-like state to catalytically convert the homologous natively-folded protein into a likeness of itself. This switch in conformation forms the basis for the infectious nature of prion proteins. The first such protein to be discovered was the cellular prion protein (PrP). Post-translational modification of native PrPc into its pathogenic isoform (PrPsc) is the molecular signature underlying a group of fatal mammalian neurodegenerative disorders (transmissible spongiform encepbalopatbies). Interestingly, recent studies on the physiological function of PrPc strongly indicate a critical role of the molecule in activation of signalling pathways linked to maintenance of mitochondrial integrity and cell survival. These include the phosphatidylinositol 3-kinase (PI3K) and mitogen-activated protein kinase (MAPK) pathways. Many interaction partners have been proposed for PrPc, but perhaps the most intriguing is its ability to bind copper(II) ions via the highly conserved Nterminal octapeptide repeat domains. Indeed, our studies were the first to suggest that copper enables triggering of PrP-dependent signalling to PI3K, which in tum acts as a modulator of neuroprotective signalling. Given that conversion of PrPc to PrPsc in prion diseases leads to PrPc deficiency, phannacological stimulation of lost PrPc signals may provide a useful treatment approach for these fatal neurological illnesses. In addition, studies on the signalling aspect of PrP underscore Lhe importance of the prion mechanism with respect to modulation of signalling pathways. Specifically, the self-sustaining confonnational propagation of the prion-like state can induce a stable alteration in a signalling pathway. Such a novel mechanism of signalling is being proposed to play important roles in biological phenomena as diverse as adaptive growth, long-tenn memory, and cancer.