Prion protein

The prion protein (PrP^C, the product of the Prnp gene) is an N-glycosylated, glycosyl phosphatidylinositol (GPI)-anchored protein of 208–209 amino acids, containing an amino (N)-terminal flexible, random coil sequence that spans approximately half of its amino-acid residues, and a carboxy (C)-terminal globular domain, the major structural features of which are remarkably preserved among both mammalian and non-mammalian species. The prion protein is highly expressed within the nervous system, although its content varies among distinct brain regions, among differing cell types and among neurochemically distinct neurons. In addition, substantial amounts of PrP^C are expressed in various cellular components of the immune system, the bone marrow, blood and peripheral tissues. Other organs and tissues, such as muscle, endocrine glands, gastrointestinal mucosa, lung and heart, also express PrP^C. Although the strength of the evidence is variable, available data indicate binding of PrP^C to several dozen distinct molecules, including proteins and glycosaminoglycans of the cell surface, various protein kinases and other components of signaling pathways, and even nucleic acids. The topology of some of these interactions is, however, debatable, and may not be relevant for physiological activities of PrP^C. The expression and the engagement of PrP^C with a variety of ligands modulate functions of the nervous and immune systems, including memory and inflammatory reactions, as well as cell proliferation, adhesion, differentiation and sensitivity to programmed cell death. The last properties have also been shown in various cell lines, where PrP^C has been shown to affect the activity of numerous signal transduction pathways. Moreover, PrP^C traffics both laterally among distinct plasma membrane domains and along endocytic pathways, and is continuously and rapidly recycled. A unified view of these functional properties suggests that the prion protein may function in a manner analogous to intracellular scaffolding proteins to act as a dynamic cell-surface platform for the assembly of signaling modules. In this view, selective interactions with many ligands and transmembrane signaling pathways would translate into wide-ranging consequences upon both physiology and behavior.