NR AFPG
AU Hosszu,L.L.P.; Baxter,N.J.; Jackson,G.S.; Power,A.; Clarke,A.R.; Waltho,J.P.; Craven,C.J.; Collinge,J.
TI Structural mobility of the human prion protein probed by backbone hydrogen exchange
QU Nature Structural Biology 1999 Aug; 6(8): 740-3
PT journal article
AB Prions, the causative agents of Creutzfeldt-Jakob Disease (CJD) in humans and bovine spongiform encephalopathy (BSE) and scrapie in animals, are principally composed of PrPsc, a conformational isomer of cellular prion protein (PrPc). The propensity of PrPc to adopt alternative folds suggests that there may be an unusually high proportion of alternative conformations in dynamic equilibrium with the native state. However, the rates of hydrogen/deuterium exchange demonstrate that the conformation of human PrPc is not abnormally plastic. The stable core of PrPc has extensive contributions from all three alpha-helices and shows protection factors equal to the equilibrium constant for the major unfolding transition. A residual, hyper-stable region is retained upon unfolding, and exchange analysis identifies this as a small nucleus of approximately 10 residues around the disulfide bond. These results show that the most likely route for the conversion of PrPc to PrPsc is through a highly unfolded state that retains, at most, only this small nucleus of structure, rather than through a highly organized folding intermediate.
MH Circular Dichroism; Human; Hydrogen/*chemistry; Magnetic Resonance Spectroscopy; Prions/*chemistry; Protein Conformation; Protein Denaturation; Support, Non-U.S. Gov't
AD [1] These authors contributed equally to this work.[2] Prion Disease Group, Department of Neurogenetics, Imperial College School of Medicine at St. Mary's, London, W2 1NY, UK
SP englisch
PO USA