PrPC Directly Interacts with Proteins Involved in Signaling Pathways

Abstract

The cellular prion protein (PrP C ) is a conserved glycoprotein predominantly expressed in neuronal cells. Its purpose in living cells is still enigmatic. To elucidate on its cellular function, we performed a yeast two-hybrid screen for interactors. We used murine PrP C (amino acids 23-231) as bait to search a mouse brain cDNA expression library. Several interaction partners were identified. Three of them with a high homology to known sequences were further characterized. These candidates were the neuronal phosphoprotein synapsin Ib, the adaptor protein Grb2, and the still uncharacterized prion interactor Pint1. The in vivo interaction of the three proteins with PrP C was confirmed by co-immunoprecipitation assays with recombinant and authentic proteins in mammalian cells. The binding regions were mapped using truncated PrP constructs. As both synapsin Ib and Grb2 are implicated in neuronal signaling processes, our findings further strengthen the putative role of the prion protein in signal transduction.

New insights into cellular prion protein (PrPc) functions: The “ying and yang” of a relevant protein

“…In this regard, the vesicle-associated protein Synapsin Ib has been reported to interact with PrP c ; which may supports this hypothesis (Spielhaupter and Schatzl, 2001). In addition, PrP c , by Cu 2+ binding, may participate in the control of calcium flux and redox stage of the presynaptic terminal (Vassallo and Herms, 2003).…”

“…Most of the interactions have been determined by coimmunoprecipitation, two-yeast assays or other biochemical techniques. Among the myriad of interactions described, Hsp60 (Edenhofer et al, 1996), STI1 (Zanata et al, 2002), Bcl-2 (Kurschner and Morgan, 1995), and Grb2 (Spielhaupter and Schatzl, 2001) have been proposed as PrP c ligands. However, only a small proportion of these related pathways are functional in a physiological context (see (Lee et al, 2003) or (Westergard et al, 2007) and (Linden et al, 2008) for reviews).…”

“…This data is crucial since it linked the survival properties of PrP c to a specific signaling pathway. In this regard, the yeast two-hybrid system pointed to Grb2 and other proteins as interactive partners in signal transduction, although this interaction has not been fully demonstrated in functional terms (Spielhaupter and Schatzl, 2001). The second set of studies was conducted by V.R.…”

Absence of the Cellular Prion Protein Exacerbates and Prolongs Neuroinflammation in Experimental Autoimmune Encephalomyelitis

“…2,3 PrP C may serve as a receptor for a variety of putative ligands, including: heparan sulfate, 4 laminin, 5 neural cell adhesion molecule, 6 various synaptic proteins, 7 and stressinducible protein-1. 8 These ligand-receptor interactions suggest that PrP C could have a role in diverse processes, including neurodevelopment, synaptic function, neurite outgrowth, and neuronal survival.…”

Misfolding of the prion protein: linking biophysical and biological approaches

“…Some intracellular proteins like Bcl-2 having an anti-apoptotic function and several other proteins without defined functions such as Pli, [129] and Pint1 [115] interact with PrP. Plasminogen, found in intercellular medium and in blood, binds PrP Sc but not PrP C [67].…”