The possible role of protein X, a putative auxiliary factor in pathological prion replication, in regulating a physiological endoproteolytic cleavage of cellular prion protein

The posttranslational conformational conversion of the cellular isoform of prion protein PrPC into its scrapie isoform PrPSc is the fundamental process underlying the pathogenesis of prion disease. Based on several transgenic data, it has been postulated that a putative auxiliary factor denoted protein X functions as a molecular chaperone through its unfolding activity of PrPC during the formation of PrPSc. However, the assumption that protein X therefore exists exclusively in prion diseases appears improbable and thus, it should have some simultaneous physiological role. We, hereby, propose a novel concept - a characteristic role of protein X in supporting a physiological endoproteolytic cleavage of PrPC. The events corresponding to the formation of the physiologically metabolized PrPC or the pathologically transformed PrPSc are mutually exclusive. Amino acid residues that are critical in terms of the target site of protein X for the pathological alteration into PrPSc overlap at the cleavage site. These amino acid residues tend to have a hydrophobic property and are most probably found buried inside the native protein structure. Therefore, a putative molecular chaperone identical to protein X may target the same hydrophobic residues in PrPC and work in conjunction with either PrPSc in prion disease or PrP proteases during the physiological state. This postulation may help explain in a relatively simple manner these two mutually exclusive phenomena, viz. the physiological endoproteolytic cleavage of PrPC and its pathological conversion into PrPSc.