Prion diseases are characterized by the intraneuronal accumulation of a pathological isoform (PrP(Sc)) of host-encoded prion protein (PrP(C)). While PrP(Sc) displays a partial resistance, PrP(C) is easily degraded by this enzyme. As it turned out in our experiments, PrP(C) of six species is initially degraded to an intermediate fragment of 25-28 kDa prior to complete proteolysis which was solely detected by antibodies binding to epitopes carboxy-terminally of amino acid 144 of PrP(C). The intermediate fragment thus lacked the aminoterminus of PrP(C). These findings are well in line with the putative structure of PrP(C): the amino-terminus consists of a highly flexible and thus more proteinase K sensitive tail while the carboxy-terminus is folded into possibly more resistant alpha-helices and beta-sheets. We observed significant differences in the PK sensitivities of PrP(C) from six different species and from three ovine PrP alleles, while no remarkable variation was seen in PrP(C) from six regions of an ovine brain. This indicates that variations in the sequence of PrP may alter its three-dimensional structure and consequently change its sensitivity towards proteolytic enzymes.