title: Inter-oligomer interactions of the human prion protein are modulated by the polymorphism at codon 129.
abstract: The common polymorphism at codon 129 in the human prion protein (PrP) has been shown in many studies to influence not only the pathology of prion disease but also the misfolding propensity of PrP. Here we used NMR, CD and atomic force microscopy in solution to investigate differences in beta-oligomer (beta(O)) formation and inter-oligomer interaction depending on the polymorphism at codon 129. NMR investigations assigned the observable amide resonances to the beta(O) N-terminal segments, showing that it is the core region of PrP (residues 127-228) that is involved in beta(O) formation. Atomic force microscopy revealed distinctive 1.8 x 15 x 15-nm disk-like structures that form stacks through inter-oligomer interactions. The propensity to form stacks and the number of oligomers involved depended on the polymorphism at codon 129, with a significantly lower degree of stacking for beta(O) with valine at position 129. This result provides evidence for conformational differences between the beta(O) allelic forms, showing that the core region of the protein including position 129 is actively involved in inter-oligomer interactions, consistent with NMR observations.
authors.affiliation: Department of Chemistry, Physical and Theoretical Chemistry Laboratory, University of Oxford, South Parks Road, Oxford OX1 3QZ, UK. remo.gerber@lincoln.oxon.org
authors.forename: Remo
authors.initials: R
authors.lastname: Gerber
authors.forename: Kislon
authors.initials: K
authors.lastname: Voitchovsky
authors.forename: Clement
authors.initials: C
authors.lastname: Mitchel
authors.forename: Abdessamad
authors.initials: A
authors.lastname: Tahiri-Alaoui
authors.forename: John F
authors.initials: JF
authors.lastname: Ryan
authors.forename: P J
authors.initials: PJ
authors.lastname: Hore
authors.forename: William
authors.initials: W
authors.lastname: James
mesh_terms: D002851:Chromatography, High Pressure Liquid; D002942:Circular Dichroism; D003062:Codon / Q000235:genetics*; D006801:Humans; D018625:Microscopy, Atomic Force; D019906:Nuclear Magnetic Resonance, Biomolecular; D011110:Polymorphism, Genetic / Q000235:genetics*; D011328:Prions / Q000235:genetics* / Q000378:metabolism* / Q000648:ultrastructure; D011485:Protein Binding; D011489:Protein Denaturation
chemical_list: D003062:Codon; D011328:Prions