title: Diversity in prion protein oligomerization pathways results from domain expansion as revealed by hydrogen/deuterium exchange and disulfide linkage.
abstract: The prion protein (PrP) propensity to adopt different structures is a clue to its biological role. PrP oligomers have been previously reported to bear prion infectivity or toxicity and were also found along the pathway of in vitro amyloid formation. In the present report, kinetic and structural analysis of ovine PrP (OvPrP) oligomerization showed that three distinct oligomeric species were formed in parallel, independent kinetic pathways. Only the largest oligomer gave rise to fibrillar structures at high concentration. The refolding of OvPrP into these different oligomers was investigated by analysis of hydrogen/deuterium exchange and introduction of disulfide bonds. These experiments revealed that, before oligomerization, separation of contacts in the globular part (residues 127-234) occurred between the S1-H1-S2 domain (residues 132-167) and the H2-H3 bundle (residues 174-230), implying a conformational change of the S2-H2 loop (residues 168-173). The type of oligomer to be formed depended on the site where the expansion of the OvPrP monomer was initiated. Our data bring a detailed insight into the earlier conformational changes during PrP oligomerization and account for the diversity of oligomeric entities. The kinetic and structural mechanisms proposed here might constitute a physicochemical basis of prion strain genesis.
authors: Virologie et Immunologie Moléculaires, Institut National de la Recherche Agronomique, F-78352 Jouy-en-Josas, France.
authors: Frederic
authors: F
authors: Eghiaian
authors: Thorsten
authors: T
authors: Daubenfeld
authors: Yann
authors: Y
authors: Quenet
authors: Marieke
authors: M
authors: van Audenhaege
authors: Anne-Pascale
authors: AP
authors: Bouin
authors: Guillaume
authors: G
authors: van der Rest
authors: Jeanne
authors: J
authors: Grosclaude
authors: Human
authors: H
authors: Rezaei
mesh_terms: D000818:Animals; D041961:Deuterium Exchange Measurement; D004220:Disulfides / Q000737:chemistry* / Q000378:metabolism*; D006358:Hot Temperature; D007700:Kinetics; D008854:Microscopy, Electron; D008958:Models, Molecular; D011328:Prions / Q000737:chemistry* / Q000302:isolation & purification / Q000378:metabolism* / Q000648:ultrastructure; D020836:Protein Structure, Quaternary; D017434:Protein Structure, Tertiary; D012756:Sheep
chemical_list: D004220:Disulfides; D011328:Prions