Prion diseases are fatal neurodegenerative disorders related to the conformational alteration of the prion protein (PrPC) into a pathogenic and protease-resistant isoform PrPSc. PrPC 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 (chPrPC) shares about 30% of identity in its primary sequence with mammal PrPC. 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 α-helices, one short 310-helix and a short antiparallel β-sheet. Despite this structural similarity, it should be noted that the normal isoform of mammalian PrPC is totally degraded by proteinase K, while avian PrPC 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 metaldriven conformational alteration, copper binding modes and the superoxide dismutase-like (SODlike) activity of the related copper(II) complexes.
D. La Mendola, A. Pietropaolo, G. Pappalardo, C. Zannoni, E. Rizzarelli (2008). Prion Proteins Leading to Neurodegeneration. CURRENT ALZHEIMER RESEARCH, 5, 579-590 [10.2174/156720508786898415].
Prion Proteins Leading to Neurodegeneration
PIETROPAOLO, ADRIANA;ZANNONI, CLAUDIO;
2008
Abstract
Prion diseases are fatal neurodegenerative disorders related to the conformational alteration of the prion protein (PrPC) into a pathogenic and protease-resistant isoform PrPSc. PrPC 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 (chPrPC) shares about 30% of identity in its primary sequence with mammal PrPC. 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 α-helices, one short 310-helix and a short antiparallel β-sheet. Despite this structural similarity, it should be noted that the normal isoform of mammalian PrPC is totally degraded by proteinase K, while avian PrPC 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 metaldriven conformational alteration, copper binding modes and the superoxide dismutase-like (SODlike) activity of the related copper(II) complexes.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
