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 PrP(C) into its scrapie isoform PrP(Sc) 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 PrP(C) during the formation of PrP(Sc). 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 PrP(C). The events corresponding to the formation of the physiologically metabolized PrP(C) or the pathologically transformed PrP(Sc) are mutually exclusive. Amino acid residues that are critical in terms of the target site of protein X for the pathological alteration into PrP(Sc) 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 PrP(C) and work in conjunction with either PrP(Sc) 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 PrP(C) and its pathological conversion into PrP(Sc).