The human prion protein (PrP) has a common polymorphism at residue 129, which can be valine or methionine. This polymorphism has a strong influence on susceptibility to prion diseases and on prion-strain properties. Previous work has shown that this amino acid variation has no measurable effect on the native structure of cellular PrP (PrPC). Here, it is shown that the polymorphism does not change the efficiency of conversion to the β-PrP conformation or affect the binding of copper(II) ions. However, in a partially denatured conformation, the polymorphic variation has a profound influence on the ability of the protein to form amyloid fibrils spontaneously.
AsanteE. A.,
LinehanJ. M.,
DesbruslaisM.& 8 other authors2002; BSE prions propagate as either variant CJD-like or sporadic CJD-like prion strains in transgenic mice expressing human prion protein. EMBO J 21:6358–6366[CrossRef]
BaskakovI.,
DistererP.,
BreydoL.,
ShawM.,
GillA.,
JamesW.,
Tahiri-AlaouiA.2005; The presence of valine at residue 129 in human prion protein accelerates amyloid formation. FEBS Lett 579:2589–2596[CrossRef]
CollingeJ.,
PalmerM. S.,
SidleK. C. L.& 7 other authors1995; Unaltered susceptibility to BSE in transgenic mice expressing human prion protein. Nature 378:779–783[CrossRef]
CollingeJ.,
BeckJ.,
CampbellT.,
EstibeiroK.,
WillR. G.1996a; Prion protein gene analysis in new variant cases of Creutzfeldt-Jakob disease. Lancet 348:56
CollingeJ.,
SidleK. C. L.,
MeadsJ.,
IronsideJ.,
HillA. F.1996b; Molecular analysis of prion strain variation and the aetiology of ‘new variant’ CJD. Nature 383:685–690[CrossRef]
DawsonR. M. C.,
ElliotD.,
ElliotW.,
JonesK. M.1986; Data for Biochemical Research
. , 3rd edn. pp 399–415 Oxford: Clarendon Press;
DlouhyS. R.,
HsiaoK.,
FarlowM. R.,
ForoudT.,
ConneallyP. M.,
JohnsonP.,
PrusinerS. B.,
HodesM. E.,
GhettiB.1992; Linkage of the Indiana kindred of Gerstmann–Sträussler–Scheinker disease to the prion protein gene. Nat Genet 1:64–67[CrossRef]
GoldfarbL. G.,
PetersenR. B.,
TabatonM.& 18 other authors1992; Fatal familial insomnia and familial Creutzfeldt-Jakob disease: disease phenotype determined by a DNA polymorphism. Science 258:806–808[CrossRef]
HainfellnerJ. A.,
ParchiP.,
KitamotoT.,
JariusC.,
GambettiP.,
BudkaH.1999; A novel phenotype in familial Creutzfeldt-Jakob disease: prion protein gene E200K mutation coupled with valine at codon 129 and type 2 protease-resistant prion protein. Ann Neurol 45:812–816[CrossRef]
HillA. F.,
ButterworthR. J.,
JoinerS.& 12 other authors1999; Investigation of variant Creutzfeldt-Jakob disease and other human prion diseases with tonsil biopsy samples. Lancet 353:183–189[CrossRef]
HillA. F.,
JoinerS.,
WadsworthJ. D. F.,
SidleK. C. L.,
BellJ. E.,
BudkaH.,
IronsideJ. W.,
CollingeJ.2003; Molecular classification of sporadic Creutzfeldt–Jakob disease. Brain 126:1333–1346[CrossRef]
HosszuL. L. P.,
JacksonG. S.,
TrevittC. R.& 7 other authors2004; 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
. J Biol Chem 279:28515–28521[CrossRef]
JacksonG. S.,
HosszuL. L. P.,
PowerA.& 7 other authors1999; Reversible conversion of monomeric human prion protein between native and fibrilogenic conformations. Science 283:1935–1937[CrossRef]
JacksonG. S.,
MurrayI.,
HosszuL. L. P.,
GibbsN.,
WalthoJ. P.,
ClarkeA. R.,
CollingeJ.2001; Location and properties of metal-binding sites on the human prion protein. Proc Natl Acad Sci U S A 98:8531–8535[CrossRef]
Khalili-ShiraziA.,
SummersL.,
LinehanJ.,
MallinsonG.,
AnsteeD.,
HawkeS.,
JacksonG. S.,
CollingeJ.2005b; PrP glycoforms are associated in a strain-specific ratio in native PrPSc
. J Gen Virol 86:2635–2644[CrossRef]
LeeH.-S.,
BrownP.,
CervenákováL.,
GarrutoR. M.,
AlpersM. P.,
GajdusekD. C.,
GoldfarbL. G.2001; Increased susceptibility to kuru of carriers of the PRNP 129 methionine/methionine genotype. J Infect Dis 183:192–196[CrossRef]
MeadS.,
StumpfM. P. H.,
WhitfieldJ.& 8 other authors2003; Balancing selection at the prion protein gene consistent with prehistoric kurulike epidemics. Science 300:640–643[CrossRef]
MonariL.,
ChenS. G.,
BrownP.& 12 other authors1994; Fatal familial insomnia and familial Creutzfeldt–Jakob disease: different prion proteins determined by a DNA polymorphism. Proc Natl Acad Sci U S A 91:2839–2842[CrossRef]
PanK.-M.,
BaldwinM.,
NguyenJ.& 8 other authors1993; Conversion of α -helices into β -sheets features in the formation of the scrapie prion proteins. Proc Natl Acad Sci U S A 90:10962–10966[CrossRef]
ParkerM. J.,
SpencerJ.,
ClarkeA. R.1995; An integrated kinetic analysis of intermediates and transition states in protein folding reactions. J Mol Biol 253:771–786[CrossRef]
ShibuyaS.,
HiguchiJ.,
ShinR. W.,
TateishiJ.,
KitamotoT.1998; Codon 219 Lys allele of PRNP is not found in sporadic Creutzfeldt-Jakob disease. Ann Neurol 43:826–828[CrossRef]
Tahiri-AlaouiA.,
GillA. C.,
DistererP.,
JamesW.2004; Methionine 129 variant of human prion protein oligomerizes more rapidly than the valine 129 variant: implications for disease susceptibility to Creutzfeldt-Jakob disease. J Biol Chem 279:31390–31397[CrossRef]
WadsworthJ. D. F.,
AsanteE. A.,
DesbruslaisM.& 9 other authors2004; Human prion protein with valine 129 prevents expression of variant CJD phenotype. Science 306:1793–1796[CrossRef]