title: The oligomerization properties of prion protein are restricted to the H2H3 domain.
abstract: The propensity of the prion protein (PrP) to adopt different structures is a clue to its pathological behavior. The determination of the region involved in the PrP(C) to PrP(Sc) conversion is fundamental for the understanding of the mechanisms underlying this process at the molecular level. In this paper, the polymerization of the helical H2H3 domain of ovine PrP (OvPrP) was compared to the full-length construct (using chromatography and light scattering). We show that the oligomerization patterns are identical, although the H2H3 domain has a higher polymerization rate. Furthermore, the depolymerization kinetics of purified H2H3 oligomers compared to those purified from the full-length PrP reveal that regions outside H2H3 do not significantly contribute to the oligomerization process. By combining rational mutagenesis and molecular dynamics to investigate the early stages of H2H3 oligomerization, we observe a conformationally stable beta-sheet structure that we propose as a possible nucleus for oligomerization; we also show that single point mutations in H2 and H3 present structural polymorphisms and oligomerization properties that could constitute the basis of species or strain variability.
authors.affiliation: Institut National de la Recherche Agronomique, Virologie et Immunologie Moléculaires, INRA, F-78352 Jouy-en-Josas, France.
authors.forename: Nesrine
authors.initials: N
authors.lastname: Chakroun
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Prigent
authors.forename: Cécile A
authors.initials: CA
authors.lastname: Dreiss
authors.forename: Sylvie
authors.initials: S
authors.lastname: Noinville
authors.forename: Céline
authors.initials: C
authors.lastname: Chapuis
authors.forename: Franca
authors.initials: F
authors.lastname: Fraternali
authors.forename: Human
authors.initials: H
authors.lastname: Rezaei
mesh_terms: D000818:Animals; D002850:Chromatography, Gel; D056004:Molecular Dynamics Simulation; D011328:Prions / Q000737:chemistry* / Q000235:genetics; D055503:Protein Multimerization; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D012756:Sheep
chemical_list: D011328:Prions