One O-linked sugar can affect the coil-to-beta structural transition of the prion peptide.

It has been known that the structural transition from PrP(C) to PrP(Sc) leads to the prion formation. This putative conformational change challenges the central dogma of the protein folding theory-"one sequence, one structure." Generally, scientists believe that there must be either a posttranslational modification or environmental factors involved in this event. However, all of the efforts to solve the mystery of the PrP(C) to PrP(Sc) transition have ended in vain so far. Here we provide evidence linking O-linked glycosylation to the structural transition based on prion peptide studies. We find that the O-linked alpha-GalNAc at Ser-135 suppresses the formation of amyloid fibril formation of the prion peptide at physiological salt concentrations, whereas the peptide with the same sugar at Ser-132 shows the opposite effect. Moreover, this effect is sugar specific. Replacing alpha-GalNAc with beta-GlcNAc does not yield the same effect.