NR AQKR
AU Hosszu,L.L.P.; Jackson,G.S.; Trevitt,C.R.; Jones,S.; Batchelor,M.; Bhelt,D.; Prodromidou,K.; Clarke,A.R.; Waltho,J.P.; Collinge,J.
TI The residue 129 polymorphism in human prion protein does not confer susceptibility to Creutzfeldt-Jakob disease by altering the structure or global stability of PrPc
QU The Journal of Biological Chemistry 2004 Jul 2; 279(27): 28515-21
PT journal article
AB There are two common forms of prion protein (PrP) in humans, with either methionine or valine at position 129. This polymorphism is a powerful determinant of the genetic susceptibility of humans toward both sporadic and acquired forms of prion disease and restricts propagation of particular prion strains. Despite its key role, we have no information on the effect of this mutation on the structure, stability, folding, and dynamics of the cellular form of PrP (PrPc). Here, we show that the mutation has no measurable effect on the folding, dynamics, and stability of PrPc. Our data indicate that the 129M/V polymorphism does not affect prion propagation through its effect on PrPc; rather, its influence is likely to be downstream in the disease mechanism. We infer that the M/V effect is mediated through the conformation or stability of disease-related PrP (PrPsc) or intermediates or on the kinetics of their formation.
MH Amides/chemistry; Circular Dichroism; Creutzfeldt-Jakob Syndrome/*genetics; Escherichia coli/metabolism; Genetic Predisposition to Disease; Human; Kinetics; Magnetic Resonance Spectroscopy; Methionine/chemistry; Models, Molecular; Mutation; Plasmids/metabolism; *Polymorphism (Genetics); PrPc Proteins/chemistry/*genetics; Protein Conformation; Protein Folding; Protein Structure, Secondary; Protein Structure, Tertiary; Support, Non-U.S. Gov't; Time Factors; Valine/chemistry
AD Medical Research Council Prion Unit, Department of Neurodegenerative Disease, Institute of Neurology, University College London, Queen Square, London WC1N 3BG, United Kingdom.
SP englisch
PO USA