Regulation of PrP(C) signaling and processing by dimerization.

Xavier Roucou

doi:10.3389/fcell.2014.00057

Abstract

The cellular prion protein (PrPC) is a glycosylphosphatidylinositol (GPI)-anchored protein present at the cell surface. PrPC 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 PrPC-activated signaling pathways. Remarkably, PrPC may be inactivated either by physiological endoproteolysis and release of the N-terminal domain, or by ectodomain shedding. Ligand-induced PrPC dimerization or enforced dimerization of PrPC indicate that PrPC dimerization represents an important molecular switch for both intracellular signaling and inactivation by the release of PrPC N-terminal domain or shedding. In this review, we summarize evidence that cell surface receptor activity of PrPC is finely regulated by dimerization.

Highlights

PrPC is a cell surface protein with a bipartite structure: theN-terminal domain is disordered and the C-terminal domain is structured and contains three α-helices and two short β-strands (Wuthrich and Riek, 2001)
Ligand-induced PrPC dimerization or enforced dimerization of PrPC indicate that PrPC dimerization represents an important molecular switch for both intracellular signaling and inactivation by the release of PrPC N-terminal domain or shedding
We summarize evidence that cell surface receptor activity of PrPC is finely regulated by dimerization

Summary

Xavier Roucou*

PrPC 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 PrPC-activated signaling pathways. PrPC may be inactivated either by physiological endoproteolysis and release of the N-terminal domain, or by ectodomain shedding. Ligand-induced PrPC dimerization or enforced dimerization of PrPC indicate that PrPC dimerization represents an important molecular switch for both intracellular signaling and inactivation by the release of PrPC N-terminal domain or shedding. We summarize evidence that cell surface receptor activity of PrPC is finely regulated by dimerization

INTRODUCTION

DETECTION OF PrPC DIMERS IN NATIVE CONDITIONS AND

ENDOPROTEOLYTIC EVENTS

CONCLUSION