Glycosylation influences cross‐species formation of protease‐resistant prion protein

A key event in the transmissible spongiform encephalopathies (TSEs) is the formation of aggregated and protease‐resistant prion protein, PrP‐res, from a normally soluble, protease‐sensitive and glycosylated precursor, PrP‐sen. While amino acid sequence similarity between PrP‐sen and PrP‐res influences both PrP‐res formation and cross‐species transmission of infectivity, the influence of co‐ or post‐translational modifications to PrP‐sen is unknown. Here we report that, if PrP‐sen and PrP‐res are derived from different species, PrP‐sen glycosylation can significantly affect PrP‐res formation. Glycosylation affected PrP‐res formation by influencing the amount of PrP‐sen bound to PrP‐res, while the amino acid sequence of PrP‐sen influenced the amount of PrP‐res generated in the post‐binding conversion step. Our results show that in addition to amino acid sequence, co‐ or post‐translational modifications to PrP‐sen influence PrP‐res formation in vitro . In vivo , these modifications might contribute to the resistance to infection associated with transmission of TSE infectivity across species barriers.