Genetic influence on the structural variations of the abnormal prion protein

Prion diseases are characterized by the presence of the abnormal prion prot ein PrPSc, which is believed to be generated by the conversion of the alpha -helical structure that predominates in the normal PrP isoform into a beta- sheet structure resistant to proteinase K (PK). In human prion diseases, tw o major types of PrPSc, type 1 and 2, can be distinguished based on the dif ference in electrophoretic migration of the PK-resistant core fragment. In this study, protein sequencing was used to identify the PK cleavage sites o f PrPSc in 36 cases of prion diseases. We demonstrated two primary cleavage sites at residue 82 and residue 97 for type 1 and type 2 PrPSc, respective ly, and numerous secondary cleavages distributed along the region spanning residues 74-102. Accordingly, we identify three regions in PrPSc: one N-ter minal (residues 23-73) that is invariably PK-sensitive, one C-terminal (res idues 103-231) that is invariably PK-resistant, and a third variable region (residues 74-102) where the site of the PK cleavage, likely reflecting the extent of the beta-sheet structure, varies mostly as a function of the PrP genotype at codon 129.