Conserved stress-protective activity between prion protein and Shadoo

Abstract

Shadoo (Sho) is a neuronally expressed glycoprotein of unknown function. Although there is no overall sequence homology to the cellular prion protein (PrPC), both proteins contain a highly conserved internal hydrophobic domain (HD) and are tethered to the outer leaflet of the plasma membrane via a C-terminal glycosylphosphatidylinositol anchor. A previous study revealed that Sho can reduce toxicity of a PrP mutant devoid of the HD (PrPΔHD). We have now studied the stress-protective activity of Sho in detail and identified domains involved in this activity. Like PrPC, Sho protects cells against physiological stressors such as the excitotoxin glutamate. Moreover, both PrPC and Sho required the N-terminal domain for this activity; the stress-protective capacity of PrPΔN as well as ShoΔN was significantly impaired. In both proteins, the HD promoted homodimer formation; however, deletion of the HD had different effects. Although ShoΔHD lost its stress-protective activity, PrPΔHD acquired a neurotoxic potential. Finally, we could show that the N-terminal domain of PrPC could be functionally replaced by that of Sho, suggesting a similar function of the N termini of Sho and PrPC. Our study reveals a conserved physiological activity between PrPC and Sho to protect cells from stress-induced toxicity and suggests that Sho and PrPC might act on similar signaling pathways. © 2011 by The American Society for Biochemistry and Molecular Biology, Inc.