Abstract
The prion protein, PrP, can adopt at least 2 conformations, the overwhelmingly prevalent cellular conformation (PrPC) and the scrapie conformation (PrPSc). PrPC features a globular C-terminal domain containing 3 α-helices and a short β-sheet and a long flexible N-terminal tail whose exact conformation in vivo is not yet known and a metastable subdomain with β-strand propensity has been identified within it. The PrPSc conformation is very rare and has the characteristics of an amyloid. Furthermore, PrPSc is a prion, i.e., it is infectious. This involves 2 steps: (1) PrPSc can template PrPC and coerce it to adopt the PrPSc conformation and (2) PrPSc can be transmitted between individuals, by oral, parenteral, and other routes and thus propagate as an infectious agent. However, this is a simplification: On the one hand, PrPSc is not a single conformation, but rather, a set of alternative similar but distinct conformations. Furthermore, other amyloid conformations of PrP exist with different biochemical and propagative properties. In this issue of PLOS Biology, Asante and colleagues describe the first murine model of familial human prion disease and demonstrate the emergence and propagation of 2 PrP amyloid conformers. Of these, one causes neurodegeneration, whereas the other does not. With its many conformers, PrP is a truly protean protein.
Highlights
CIMUS Biomedical Research Institute & Department of Medical Sciences, University of Santiago de Compostela-IDIS, Santiago de Compostela, Spain
PrPSc is partially resistant to proteinase K (PK), which trims its supposedly flexible N-terminal tail, generating a characteristic triplet of variably glycosylated resistant fragments termed PrP27-30. Small amounts of such triplet were seen in the infectious brain samples from PrP 117V tg mice, but only under certain circumstances, indicating that PrPSc exists in these brains but that it exhibits an unusually low resistance to PK [15] (Fig 2)
Vanni and colleagues partially isolated the PK-resistant material and showed it to contain all the infectivity harbored in these brains [17]. These results strongly suggest that the infectivity in their model is associated with the PrP conformer that yields the approximately 8-kDa doubly truncated PK-resistant band
Summary
Other amyloid conformations of PrP exist with different biochemical and propagative properties. In this issue of PLOS Biology, Asante and colleagues describe the first murine model of familial human prion disease and demonstrate the emergence and propagation of 2 PrP amyloid conformers. PrPSc prions propagate by templating their peculiar conformation into PrPC.
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