title: Prion proteins leading to neurodegeneration.
abstract: Prion diseases are fatal neurodegenerative disorders related to the conformational alteration of the prion protein (PrP C) into a pathogenic and protease-resistant isoform PrP(Sc). PrP(C) is a cell surface glycoprotein expressed mainly in the central nervous system and despite numerous efforts to elucidate its physiological role, the exact biological function remains unknown. Many lines of evidences indicate that prion is a copper binding protein and thus involved in the copper metabolism. Prion protein is not expressed only in mammals but also in other species such as birds, reptiles and fishes. However, it is noteworthy to point out that prion diseases are only observed in mammals while they seem to be spared to other species. The chicken prion protein (chPrP C) shares about 30% of identity in its primary sequence with mammal PrP C. Both types of proteins have an N-terminal domain endowed with tandem amino acid repeats (PHNPGY in the avian protein, PHGGGWQ in mammals), followed by a highly conserved hydrophobic core. Furthermore, NMR studies have highlighted a similar globular domain containing three alpha-helices, one short 3(10)-helix and a short antiparallel beta-sheet. Despite this structural similarity, it should be noted that the normal isoform of mammalian PrP C is totally degraded by proteinase K, while avian PrP C is not, thereby producing N-terminal domain peptide fragments stable to further proteolysis. Notably, the hexarepeat domain is considered essential for protein endocytosis, and it is supposed to be the analogous copper-binding octarepeat region of mammalian prion proteins. The number of copper binding sites, the affinity and the coordination environment of metal ions are still matter of discussion for both mammal and avian proteins. In this review, we summarize the similarities and the differences between mammalian and avian prion proteins, as revealed by studies carried out on the entire protein and related peptide fragments, using a range of experimental and computational approaches. In addition, we report the metal-driven conformational alteration, copper binding modes and the superoxide dismutase-like (SOD-like) activity of the related copper(II) complexes.
authors.affiliation: CNR-Instituto di Biostrutture e Bioimmagini-Catania, Catania, Italy.
authors.forename: D
authors.initials: D
authors.lastname: La Mendola
authors.forename: D L
authors.initials: DL
authors.lastname: Mendola
authors.forename: A
authors.initials: A
authors.lastname: Pietropaolo
authors.forename: G
authors.initials: G
authors.lastname: Pappalardo
authors.forename: C
authors.initials: C
authors.lastname: Zannoni
authors.forename: E
authors.initials: E
authors.lastname: Rizzarelli
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D002645:Chickens; D006801:Humans; D008670:Metals / Q000737:chemistry / Q000378:metabolism; D008958:Models, Molecular; D008969:Molecular Sequence Data; D019636:Neurodegenerative Diseases / Q000235:genetics* / Q000378:metabolism; D011328:Prions / Q000235:genetics* / Q000378:metabolism; D011487:Protein Conformation
chemical_list: D008670:Metals; D011328:Prions