Regulation of PrP(C) signaling and processing by dimerization

Abstract

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.

Keywords: dimerization; neurodegeneration; neuroprotection; prion protein trafficking; signaling.

Figure 1

PrP^C Dimerization activates a neuroprotective signaling pathway and the production of neuroprotective PrP^C-derived metabolites. En route to the plasma membrane, a fraction of PrP^C undergoes a physiological cleavage termed α-cleavage. Intracellular PrP^C dimerization stimulates trafficking to the plasma membrane and the release of PrPN1 and PrPC1 at the cell surface. PrP^C dimerization at the cell surface activates an intracellular signaling pathway with a neuroprotective outcome. At the cell surface, a fraction of PrP^C undergoes ADAM10-mediated shedding. Double arrows indicate dimerization; dotted arrow indicates shedding. See text for details.