In silico investigation of the prion protein glycosylation profiles in relation to scrapie disease resistance in domestic sheep (Ovis aries).

The prion protein is a membrane-bound glycoprotein which consists mainly α-helix structure. In contrast, the infectious prion protein shows the beta-sheet structure. The prion-associated diseases are all lethal neurodegenerative abnormalities, called transmissible spongiform encephalopathies. Scrapie is the most common type of these illnesses affecting sheep, goats, and moufflon. The VRQ, AHQ, ARR and N146S polymorphisms in the sheep prion gene have been found to be associated with resistance to scrapie disease. So far, the relationship of polymorphisms to three-dimensional protein structures, post-translational modifications, and scrapie resistance has not been studied. In this study, the potential N- and O-glycosylation positions of sheep prion protein polymorphisms were analyzed, the secondary and three-dimensional protein structure models were predicted, three-dimensional glycoprotein models were constructed and the role of glycosylation positions in protein interactions was investigated. Here, we found that protein secondary and three-dimensional structures vary among polymorphisms. Moreover, we found wild-type prion and all polymorphic variants show N-glycosylation at Asn184 and Asn200 positions, while O-glycosylation profiles are variant-specific. We also found that structural changes among prion polymorphisms leads to the formation of variant spesific O-glycosylation profiles and these positions are associated with protein interactions. Based on these findings, we suggest that O-glycosylation may be effective on resistance/susceptibility of sheep prion polymorphisms to scrapie disease.