Prion protein (PrP-c) [2572197, 1916104, 2908696] is a small glycoprotein found in high
quantity in the brain of animals infected with certain degenerative neurological diseases, such as
sheep scrapie and bovine spongiform encephalopathy (BSE), and the human dementias Creutzfeldt-Jacob
disease (CJD) and Gerstmann-Straussler syndrome (GSS). PrP-c is encoded in the host genome and is
expressed both in normal and infected cells. During infection, however, the PrP-c molecule become
altered (conformationally rather than at the amino acid level) to an abnormal isoform, PrP-sc. In detergent-treated brain extracts from infected individuals, fibrils
composed of polymers of PrP-sc, namely scrapie-associated fibrils or prion rods, can be evidenced by electron microscopy. The precise function of the normal PrP isoform in healthy individuals remains unknown. Several results, mainly obtained in transgenic animals, indicate that PrP-c
might play a role in long-term potentiation, in sleep physiology, in oxidative burst compensation (PrP can fix four Cu2+ through its octarepeat domain), in
interactions with the extracellular matrix (PrP-c can bind to the precursor of the laminin receptor, LRP), in apoptosis and in signal transduction (costimulation of
PrP-c induces a modulation of Fyn kinase phosphorylation) .
The normal isoform, PrP-c, is anchored at the cell membrane, in rafts, through a glycosyl phosphatidyl inositol (GPI); its half-life at the cell surface is 5 h, after which
the protein is internalised through a caveolae-dependent mechanism and degraded in the endolysosome compartment. Conversion between PrP-c and PrP-sc
occurs likely during the internalisation process.
In humans, PrP is a 253 amino acid protein, which has a molecular weight of 35¿36 kDa. It has two hexapeptides
and repeated octapeptides at the N-terminus, a disulphide bond and is associated at the C-terminus with a GPI, which enables it to anchor to the external part of the
cell membrane. The
secondary structure of PrP-c is mainly composed of alpha-helices, whereas PrP-sc is mainly beta-sheets: transconformation of alpha-helices into beta-sheets has been
proposed as the structural basis by which PrP acquires pathogenicity in TSEs. The three-dimensional structures shows the protein to be made of a globular domain which includes three alpha-helices and two small antiparallel beta-sheet
structures, and a long flexible tail whose conformation depends on the biophysical parameters of the environment. Crystals of the globular domain of PrP
have recently been obtained; their analysis suggests a possible dimerisation of the protein through the three-dimensional swapping of the C-terminal helix 3 and
rearrangement of the disulphide bond.