N-Terminal Regions of Prion Protein: Functions and Roles in Prion Diseases

The normal cellular isoform of prion protein, designated PrP(C), is constitutively converted to the abnormally folded, amyloidogenic isoform, PrP(Sc), in prion diseases, which include Creutzfeldt-Jakob disease in humans and scrapie and bovine spongiform encephalopathy in animals. PrP(C) is a membrane glycoprotein consisting of the non-structural N-terminal domain and the globular C-terminal domain. During conversion of PrP(C) to PrP(Sc), its 2/3 C-terminal region undergoes marked structural changes, forming a protease-resistant structure. In contrast, the N-terminal region remains protease-sensitive in PrP(Sc). Reverse genetic studies using reconstituted PrP(C)-knockout mice with various mutant PrP molecules have revealed that the N-terminal domain has an important role in the normal function of PrP(C) and the conversion of PrP(C) to PrP(Sc). The N-terminal domain includes various characteristic regions, such as the positively charged residue-rich polybasic region, the octapeptide repeat (OR) region consisting of five repeats of an octapeptide sequence, and the post-OR region with another positively charged residue-rich polybasic region followed by a stretch of hydrophobic residues. We discuss the normal functions of PrP(C), the conversion of PrP(C) to PrP(Sc), and the neurotoxicity of PrP(Sc) by focusing on the roles of the N-terminal regions in these topics.