A receptor for infectious and cellular prion protein

Abstract

Prions are an unconventional form of infectious agents composed only of protein and involved in transmissible spongiform encephalopathies in humans and animals. The infectious particle is composed by PrPsc which is an isoform of a normal cellular glycosyl-phosphatidylinositol (GPI) anchored protein, PrPc, of unknown function. The two proteins differ only in conformation, PrPc is composed of 40% a helix while PrPsc has 60% ß-sheet and 20% a helix structure. The infection mechanism is trigged by interaction of PrPsc with cellular prion protein causing conversion of the latters conformation. Therefore, the infection spreads because new PrPsc molecules are generated exponentially from the normal PrPc. The accumulation of insoluble PrPsc is probably one of the events that lead to neuronal death. Conflicting data in the literature showed that PrPc internalization is mediated either by clathrin-coated pits or by caveolae-like membranous domains. However, both pathways seem to require a third protein (a receptor or a prion-binding protein) either to make the connection between the GPI-anchored molecule to clathrin or to convert PrPc into PrPsc. We have recently characterized a 66-kDa membrane receptor which binds PrPc in vitro and in vivo and mediates the neurotoxicity of a human prion peptide. Therefore, the receptor should have a role in the pathogenesis of prion-related diseases and in the normal cellular process. Further work is necessary to clarify the events triggered by the association of PrPc/PrPsc with the receptor.

Fibrillar prion peptide (106–126) and scrapie prion protein hamper phagocytosis in microglia

“…This prion peptide has been reported to bind to several cell surface proteins (Martins et al, 1997;Rieger et al, 1997;Martins, 1999;Della-Bianca et al, 2001), including the PrP c itself (Brown, 2000). PrP c is bound to the external surface of the plasma membrane by a glycosylphosphatidylinositol (GPI) anchor.…”

Implications of Prion Protein Biology

“…It is found in the central nervous system (CNS) at high levels, however it is only found at low levels in muscles, immune cells and tissue, among other places ( Table 1) (Glatzel & Aguzzi, 2001). It is found in higher concentrations glycosylated on GPI, which anchors it to the cell membrane (Martins et al, 2001;Wechselberger et al, 2002;Martins et al, 2002;Guentchev et al, 2002;Klamt et al 2001;Martins, 1999;Prusiner, 1998). The Table 1…”

“…Neurons Martins et al, 2001;Wechselberger et al, 2002;Martins et al, 2002;Guentchev et al, 2002;Klamt et al, 2001;Martins, 1999;Prusiner, 1998. Immune cells Bainbridge & Walker, 2005;Jouvin-Marche et al, 2006;Martins, 1999;Glatzel & Aguzzi, 2001 physiological role of this protein is not completely understood, but due to its conservation among species, it is believed that this protein plays a major physiological role (Martins et al, 2001;Wechselberger et al, 2002;Prusiner, 1998).…”

“…PrP sc also shows resistance to proteinase K digestion where PrP c isoform and many other proteins are rapidly degraded (DeArmond, 2004). However, the "protease resistant" concept is relative because when treated with K proteinase, PrP sc produces a 27-30Kda peptide, called PrP27-30 (Martins, 1999;DeArmond 2004;Weissmann, 2004). This PrP27-30 peptide generated through PrP sc limited hidrolysis is likely to be the major, if not the only component of the pathogenic particle.…”

“…The cellular prion protein (PrP c ) is composed of approximately 250 amino acids (Martins et al, 2001;Wechselberger et al, 2002) and is found on the surface of many cellular subtypes, especially neurons, where it is anchored by a glycosyl-phosphatidylinositol residue (GPI) (Martins et al, 2001;Wechselberger et al, 2002;Martins et al, 2002;Guentchev et al, 2002;Klamt et al, 2001;Martins, 1999;Prusiner, 1998). The PrP c is highly conserved among mammals, suggesting an important physiologic role (Martins et al, 2001;Wechselberger et al, 2002;Martins et al, 2002;Prusiner, 1998).…”