Fig. 3. Models for the conformational conversion of PrPC to PrPSc. A, the "refolding" model. The conformational change is kinetically controlled, a high activation energy barrier preventing spontaneous conversion at detectable rates. Interaction with exogenously introduced PrPSc causes PrPC to undergo an induced conformational change to yield PrPSc. This reaction may involve extensive unfolding and refolding of the protein to explain the postulated high energy barrier and could be dependent on an enzyme or chaperone. In the case of certain mutations in PrPC, spontaneous conversion to PrPSc may occur as a rare event, explaining why familial CJD or GSS arises spontaneously, albeit late in life. Sporadic CJD may come about when an extremely rare event (occurring in one among a million individuals per year) leads to spontaneous conversion of PrPC to PrPSc and gives rise to a conversion cascade. B, the "seeding" model. PrPC and PrPSc (or a PrPSc-like molecule) are in equilibrium strongly favoring PrPC. PrPSc is only stabilized when it adds onto a crystal-like seed or aggregate of PrPSc. Seed formation is a rare event; once a seed is present, monomer addition can ensue at a rapid rate. To explain exponential conversion rates, it must be assumed that the aggregates are continuously fragmented to present increasing surface for accretion.
From: C. Weissmann (1999) Molecular genetics of transmissible spongiform encephalopathies. J. Biol. Chem. 274: 3-6 (html)(pdf)