Abstract
Prion disease is a neurodegenerative disorder. The prion formation, resulting from a structural conversion of the prion protein from the cellular form (PrPC) to the pathogenic isoform (PrPSc), is the culprit of the malady. A posttranslational process on the prion protein has been implicated in the prion formation during the development of prion disease. However, what the modification is and how the modification works remain elusive. It has been found that adding one single sugar on the prion peptide (sequence 108-144) can affect the structural conversion of the modified peptide and the following amyloid fibril formation. Interestingly, this effect is sugar-specific. Introducing an □a-GalNAc to Ser-135 of the prion peptide could suppress the fibrillization while adding a □b-GlcNAc did not yield the same effect. In order to understand the origin of the effect, we performed a series glycosylations with these two sugars and another two non-native isomers □b-GalNAc, and □a-GlcNAc and compared their effects on the fibrillization of the prion peptide. We found that the anomeric position is the origin of the inhibition. Either □a-GalNAc or □a-GlcNAc has more prominent effect on the conformational energy of the peptide and inhibits the assembly of the peptide to form amyloid. The NMR results showed that the region of Ser-135 and Arg-136 plays the critical point for amyloidogenesis. We also compared the influence of glycosylation and phosphorylation on fibrillization.