NR AXAJ
AU Eghiaian,F.; Daubenfeld,T.; Quenet,Y.; van Audenhaege,M.; Bouin,A.P.; van der Rest,G.; Grosclaude,J.; Rezaei,H.
TI Diversity in prion protein oligomerization pathways results from domain expansion as revealed by hydrogen/deuterium exchange and disulfide linkage
QU Proceedings of the National Academy of Sciences of the United States of America 2007 May 1; 104(18): 7414-9
PT journal article; research support, non-u.s. gov't
AB 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.
MH Animals; Deuterium Exchange Measurement; Disulfides/*chemistry/*metabolism; Heat; Kinetics; Microscopy, Electron; Models, Molecular; Prions/*chemistry/isolation & purification/*metabolism/ultrastructure; Protein Structure, Quaternary; Protein Structure, Tertiary; Sheep
AD Virologie et Immunologie Moleculaires, Institut National de la Recherche Agronomique, F-78352 Jouy-en-Josas, France.
SP englisch
PO USA