Locally disordered conformer of the hamster prion protein:: A crucial intermediate to PrPSc?

A crucial step for transformation of the normal cellular isoform of the prion protein (PrPC) to the infectious prion protein (PrPSc) is thought to entail a previously uncharacterized intermediate conformer, PrP*, which interacts with a template PrPSc molecule in the conversion process. By carrying out N-15-H-1 two-dimensional NMR measurements under variable pressure on Syrian hamster prion protein rPrP(90-231), we found a metastable conformer of PrPC coexisting at a population of similar to1% at pH 5.2 and 30 degreesC, in which helices B and C are preferentially disordered. While the identity is still unproven, this observed metastable conformer is most logically PrP* or a closely related precursor. The structural characteristics of this metastable conformer are consistent with available immunological and pathological information about the prion protein.