title: The presence of valine at residue 129 in human prion protein accelerates amyloid formation.
abstract: The polymorphism at residue 129 of the human PRNP gene modulates disease susceptibility and the clinico-pathological phenotypes in human transmissible spongiform encephalopathies. The molecular mechanisms by which the effect of this polymorphism are mediated remain unclear. It has been shown that the folding, dynamics and stability of the physiological, alpha-helix-rich form of recombinant PrP are not affected by codon 129 polymorphism. Consistent with this, we have recently shown that the kinetics of amyloid formation do not differ between protein containing methionine at codon 129 and valine at codon 129 when the reaction is initiated from the alpha-monomeric PrP(C)-like state. In contrast, we have shown that the misfolding pathway leading to the formation of beta-sheet-rich, soluble oligomer was favoured by the presence of methionine, compared with valine, at position 129. In the present work, we examine the effect of this polymorphism on the kinetics of an alternative misfolding pathway, that of amyloid formation using partially folded PrP allelomorphs. We show that the valine 129 allelomorph forms amyloids with a considerably shorter lag phase than the methionine 129 allelomorph both under spontaneous conditions and when seeded with pre-formed amyloid fibres. Taken together, our studies demonstrate that the effect of the codon 129 polymorphism depends on the specific misfolding pathway and on the initial conformation of the protein. The inverse propensities of the two allelomorphs to misfold in vitro through the alternative oligomeric and amyloidogenic pathways could explain some aspects of prion diseases linked to this polymorphism such as age at onset and disease incubation time.
authors.affiliation: Medical Biotechnology Center, University of Maryland Biotechnology Institute, Baltimore, 21201, USA.
authors.forename: Ilia
authors.initials: I
authors.lastname: Baskakov
authors.forename: Petra
authors.initials: P
authors.lastname: Disterer
authors.forename: Leonid
authors.initials: L
authors.lastname: Breydo
authors.forename: Michael
authors.initials: M
authors.lastname: Shaw
authors.forename: Andrew
authors.initials: A
authors.lastname: Gill
authors.forename: William
authors.initials: W
authors.lastname: James
authors.forename: Abdessamad
authors.initials: A
authors.lastname: Tahiri-Alaoui
mesh_terms: D000483:Alleles; D000682:Amyloid / Q000096:biosynthesis* / Q000648:ultrastructure; D002851:Chromatography, High Pressure Liquid; D002942:Circular Dichroism; D003062:Codon; D014644:Genetic Variation; D006801:Humans; D007700:Kinetics; D008715:Methionine / Q000737:chemistry; D008954:Models, Biological; D011110:Polymorphism, Genetic; D011328:Prions / Q000737:chemistry* / Q000235:genetics / Q000302:isolation & purification / Q000378:metabolism / Q000648:ultrastructure; D011487:Protein Conformation; D017510:Protein Folding; D017433:Protein Structure, Secondary; D011994:Recombinant Proteins / Q000737:chemistry / Q000302:isolation & purification / Q000378:metabolism / Q000648:ultrastructure; D017550:Spectroscopy, Fourier Transform Infrared; D014633:Valine / Q000737:chemistry*
chemical_list: D000682:Amyloid; D003062:Codon; D011328:Prions; D011994:Recombinant Proteins; D008715:Methionine; D014633:Valine