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.The prion diseases are a group of fatal neurodegenerative diseases that include scrapie in sheep and goats; bovine spongiform encephalopathy (BSE) 1 in cattle; and Creutzfeldt-Jakob disease (CJD), Gerstmann-Strä ussler-Scheinker disease, fatal familial insomnia (FFI), and kuru in humans. The human diseases may be inherited, arise sporadically, or be acquired through exposure to infectious prions (1, 2). Although rare in humans, intense interest has focused on these diseases both because of their unique biology and because of the occurrence of variant CJD, a new form of human prion disease, and the experimental evidence that it is caused by a BSE-like prion strain (3-5).According to the "protein-only" hypothesis (6), prions are composed principally or entirely of abnormal isoforms of hostencoded prion protein (PrP) (7). The disease-related isoform, PrP Sc , is derived from its normal cellular precursor, PrP C , by a post-translational process that involves conformational change. PrP Sc can be distinguished biochemically from PrP C by its partial protease resistance and detergent insolubility.Although the precise molecular events involved in this conversion remain ill defined, molecular genetic and in vitro studies support the hypothesis that some sort of direct interaction between PrP Sc and either PrP C or some less organized state occurs. This interaction results in the PrP Sc conformation being imposed upon the substrate protein, and the process of conversion is favored by sequence complementarity (8 -13). A key piece of evidence supporting this and the protein-only hypothesis in general is the finding that the large majority of cases of sporadic CJD are homozygous with respect to a common polymorphism at position 129 in the human prion protein, in which either methionine or valine can be encoded (only ϳ49% of the UK population are homozygous with respect to this polymorphism) (9).Elderly survivors of the kuru epidemic (an acquired prion disease largely restricted to the Fore linguistic group of the Papua New Guinea Highlands, which was transmitted during endocannibalistic feasts) who had mult...

A considerable body of evidence now shows that PrP (prion protein) binds metal ions with high affinity and it has been claimed that the binding of copper (II) ions to PrP confers SOD (superoxide dismutase) activity. In turn, it has been suggested that PrP is a synaptic dismutase and that loss of this function, as a result of the conversion of PrP(C) into PrP(Sc), results in pathology and hence morbidity associated with prion disease. However, contrary to previous reports, in the present study we have found that PrP exhibits no detectable dismutase activity above baseline levels measured for copper (II) ions in water when assayed using a reliable procedure with a detection limit of at least 2 units of activity/mg of protein. This was true when the assay was performed with either PrP refolded from a denatured state in the presence of copper, as in previous studies, or native PrP loaded with copper. Thus if PrP has any role in oxidative stress, it must be indirect as a regulator of protective cellular responses.

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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 (PrP C). Here, it is shown that the polymorphism does not change the efficiency of conversion to the b-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.