PrP^Sc is a protease resistant form of PrPc, both are extensively post translationally modified. No chemical differences between the two forms of the protein have been detected. Clearly there must be some difference. One great problem is that infectivity ratio is about 100,000:1, so infectious agent even if derived from PrPc may not be PrP^Sc and it could be chemically modified.

However, a more likely possibility is that the difference between PrPc and PrP^Sc is conformational. 3D structure of part of the murine PrPc expressed in E. coli has recently been determined. As expected from spectroscopy measurements PrPc is predominantly alpha helical and contains almost no beta sheet. The structure of PrP^Sc has not yet been determined but is predicted to be predominantly B- sheet. Proposed therefore that this protein can adopt 2 quite different stable conformations. The safe PrPc form is normally adopted but rarely it can switch to the PrP^Sc form. Mutations favour this switch. Propose that PrP^Sc is transdominant and converts PrPc to PrP^Sc in an exponential fashion. Precedents for this model do exist. There is a yeast mutant phenotype which doesn't correlate to any mutational difference in the gene structure but does correlate to a different protein structure. The Ure2p protein converts to an inactive conformation. Mutations in the tumour suppresser protein p53 which are associated with the onset of neoplastic disease have a different conformation to the normal protein. When normal protein is incubated with mutant protein its conformation is altered to the mutant form.

The first image below shows the structure of part of the hamster and mouse PrPc molecules superimposed. The close similarity in structures is obvious, as is the preponderance of alpha helical structure.