title: Mechanism of neurotoxicity of prion and Alzheimer's disease-related proteins: molecular insights from bioinformatically identified ω-conotoxin-like pharmacophores.
abstract: Prion diseases are fatal neurodegenerative disorders caused by altered forms of the prion protein (PrPC). It was reported that dysregulation of cellular Ca2+ homeostasis is recurrent in these diseases and that scrapie-infected cells exhibit Ca2+ perturbation via specific impairment of N-type calcium channels. However, it is not known whether such dysfunction is secondary to the broad neuronal damage accompanying prion diseases or whether it underlies pathological interactions of prions with calcium channels. In this research, we examined this latter possibility by searching for channel binding signatures in PrPC through structural comparison with known N-type channel blockers. To this aim, a computational method devised by us to recognize similar distributions of basic residues in protein structures enabled us to find that the bioactive groups representing the pharmacophores of ω-conotoxins GVIA and MVIIA can be overlaid onto similar residues within the PrPC globular domain. This finding, together with the knowledge that Ca2+ homeostasis disruption is common to other neurodegenerative disorders, led us to search for and identify an ω-conotoxin-like pharmacophore also in the Alzheimer's Aβ(1-42) peptide. These results point to the potential ability of prions and Aβ(1-42) to bind calcium channels as the elusive neurotoxic mechanism common to seemingly unrelated fatal neuropathies.
authors.affiliation: Research Laboratories, Bambino Gesù Children's Hospital, Rome, Italy.
authors.forename: Emanuele
authors.initials: E
authors.lastname: Bellacchio
mesh_terms: D016229:Amyloid beta-Peptides / Q000737:chemistry*; D000818:Animals; D019295:Computational Biology; D006801:Humans; D008958:Models, Molecular; D010446:Peptide Fragments / Q000737:chemistry*; D011328:Prions / Q000737:chemistry*; D017434:Protein Structure, Tertiary; D020960:omega-Conotoxins / Q000737:chemistry*
chemical_list: D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; D011328:Prions; C075222:amyloid beta-protein (1-42); D020960:omega-Conotoxins