Regulation of PrP ^C signaling and processing by dimerization

The cellular prion protein (PrP ^C) is a glycosylphosphatidylinositol (GPI)-anchored protein present at the cell surface. PrP ^C N-terminal moiety is intrinsically disordered and is able to interact with a variety of ligands. Physiological ligands have neurotrophic activity, whilst others, including protein toxic oligomers, have neurotoxic functions. These two opposite activities involve different interacting partners and result from different PrP ^C-activated signaling pathways. Remarkably, PrP ^C may be inactivated either by physiological endoproteolysis and release of the N-terminal domain, or by ectodomain shedding. Ligand-induced PrP ^C dimerization or enforced dimerization of PrP ^C indicate that PrP ^C dimerization represents an important molecular switch for both intracellular signaling and inactivation by the release of PrP ^C N-terminal domain or shedding. In this review, we summarize evidence that cell surface receptor activity of PrP ^C is finely regulated by dimerization.