NR ASIN
AU Baskakov,I.V.; Disterer,P.; Breydo,L.; Shaw,M.; Gill,A.; James,W.; Tahiri-Alaoui,A.
TI The presence of valine at residue 129 in human prion protein accelerates amyloid formation
QU FEBS Letters 2005 May 9; 579(12): 2589-96
IA http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6T36-4FWTYN5-6&_user=10&_coverDate=05%2F09%2F2005&_rdoc=10&_fmt=full&_orig=browse&_srch=doc-info(%23toc%234938%232005%23994209987%23594361%23FLA%23display%23Volume)&_cdi=4938&_sort=d&_docanchor=&_ct=36&_acct=C000050221&_version=1&_urlVersion=0&_userid=10&md5=e2146fdda4b7e87b3b239ef6834e39bb
PT journal article
AB 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 PrPc-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.
MH Alleles; Amyloid/*biosynthesis/ultrastructure; Chromatography, High Pressure Liquid; Circular Dichroism; Codon; Humans; Kinetics; Methionine/chemistry; Models, Biological; Polymorphism, Genetic; Prions/*chemistry/genetics/isolation &; purification/metabolism/ultrastructure; Protein Conformation; Protein Folding; Protein Structure, Secondary; Recombinant Proteins/chemistry/isolation &; purification/metabolism/ultrastructure; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, P.H.S.; Spectroscopy, Fourier Transform Infrared; Valine/*chemistry; Variation (Genetics)
AD Ilia Baskakov, Leonid Breydo, Medical Biotechnology Center, University of Maryland Biotechnology Institute, Baltimore, 21201, USA; Petra Disterer, Michael Shaw, William James Abdessamad Tahiri-Alaoui, Sir William Dunn School of Pathology, University of Oxford, South Parks Road, Oxford, OX1 3RE, UK; Andrew Gill, Institute for Animal Health, Compton, Berkshire, Newbury, RG20 7NN, UK
SP englisch
PO Niederlande