title: X-ray structural and molecular dynamical studies of the globular domains of cow, deer, elk and Syrian hamster prion proteins.
abstract: Misfolded prion proteins are the cause of neurodegenerative diseases that affect many mammalian species, including humans. Transmission of the prion diseases poses a considerable public-health risk as a specific prion disease such as bovine spongiform encephalopathy can be transferred to humans and other mammalian species upon contaminant exposure. The underlying mechanism of prion propagation and the species barriers that control cross species transmission has been investigated quite extensively. So far a number of prion strains have been characterized and those have been intimately linked to species-specific infectivity and other pathophysiological manifestations. These strains are encoded by a protein-only agent, and have a high degree of sequence identity across mammalian species. The molecular events that lead to strain differentiation remain elusive. In order to contribute to the understanding of strain differentiation, we have determined the crystal structures of the globular, folded domains of four prion proteins (cow, deer, elk and Syrian hamster) bound to the POM1 antibody fragment Fab. Although the overall structural folds of the mammalian prion proteins remains extremely similar, there are several local structural variations observed in the misfolding-initiator motifs. In additional molecular dynamics simulation studies on these several prion proteins reveal differences in the local fluctuations and imply that these differences have possible roles in the unfolding of the globular domains. These local variations in the structured domains perpetuate diverse patterns of prion misfolding and possibly facilitate the strain selection and adaptation.
authors: Department of Biochemistry, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB T6G 2H7, Canada.
authors: Pravas Kumar
authors: PK
authors: Baral
authors: Department of Biochemistry, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB T6G 2H7, Canada.
authors: Mridula
authors: M
authors: Swayampakula
authors: Department of Pathology, Institute of Neuropathology, University Hospital Zurich, Zurich, Switzerland.
authors: Adriano
authors: A
authors: Aguzzi
authors: Department of Biochemistry, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB T6G 2H7, Canada. Electronic address: michael.james@ualberta.ca.
authors: Michael N G
authors: MN
authors: James
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D002417:Cattle; D017124:Conserved Sequence; D006224:Cricetinae; D018360:Crystallography, X-Ray; D003670:Deer; D006860:Hydrogen Bonding; D064267:Intrinsically Disordered Proteins / Q000737:chemistry; D008647:Mesocricetus; D056004:Molecular Dynamics Simulation; D008969:Molecular Sequence Data; D011328:Prions / Q000737:chemistry*; D017510:Protein Folding; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D040681:Structural Homology, Protein
chemical_list: D064267:Intrinsically Disordered Proteins; D011328:Prions
keywords: Misfolding; Prion; Strain