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.
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 (PrP(C)). Here, we show that the mutation has no measurable effect on the folding, dynamics, and stability of PrP(C). Our data indicate that the 129M/V polymorphism does not affect prion propagation through its effect on PrP(C); 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 (PrP(Sc)) or intermediates or on the kinetics of their formation.
Hosszu
Laszlo L P
LL
Medical Research Council Prion Unit, Department of Neurodegenerative Disease, Institute of Neurology, University College London, Queen Square, London WC1N 3BG, United Kingdom.
Jackson
Graham S
GS
Trevitt
Clare R
CR
Jones
Samantha
S
Batchelor
Mark
M
Bhelt
Daljit
D
Prodromidou
Kanella
K
Clarke
Anthony R
AR
Waltho
Jonathan P
JP
Collinge
John
J
D000577:Amides / Q000737:chemistry; D002942:Circular Dichroism; D007562:Creutzfeldt-Jakob Syndrome / Q000235:genetics*; D004926:Escherichia coli / Q000378:metabolism; D020022:Genetic Predisposition to Disease; D006801:Humans; D007700:Kinetics; D009682:Magnetic Resonance Spectroscopy; D008715:Methionine / Q000737:chemistry; D008958:Models, Molecular; D009154:Mutation; D010957:Plasmids / Q000378:metabolism; D011110:Polymorphism, Genetic; D018621:PrPC Proteins / Q000737:chemistry / Q000235:genetics*; D011487:Protein Conformation; D017510:Protein Folding; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D013997:Time Factors; D014633:Valine / Q000737:chemistry
D000577:Amides; D018621:PrPC Proteins; D008715:Methionine; D014633:Valine