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The transmissible spongiform encephalopathies are characterized by conversion of a host protein, PrP C (cellular prion protein), to a protease-resistant isoform, PrP Sc (prion protein scrapie isoform). The importance of the highly¯exible, N-terminal region of PrP has recently become more widely appreciated, particularly the biological activities associated with its metal ion-binding domain and its potential to form a poly(L-proline) II (PPII) helix. Circular dichroism spectroscopy of an N-terminal peptide, PrP 37±53 , showed that the PPII helix is formed in aqueous buffer; as it also contains an Xaa±Pro±Gly consensus sequence, it may act as a substrate for the collagenmodifying enzyme prolyl 4-hydroxylase. Direct evidence for this modi®cation was obtained by mass spectrometry and Edman sequencing in recombinant mouse PrP secreted from stably transfected Chinese hamster ovary cells. Almost complete conversion of proline to 4-hydroxyproline occurs speci®cally at residue Pro44 of this murine protein; the same hydroxylated residue was detected, at lower levels, in PrP Sc from the brains of scrapie-infected mice. Cation binding and/or post-translational hydroxylation of this region of PrP may regulate its role in the physiology and pathobiology of the cell.

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