Prion infection is characterized by the conversion of host cellular prion protein (PrP C ) into disease-related conformers (PrP Sc ) and can be arrested in vivo by passive immunization with anti-PrP monoclonal antibodies. Here, we show that the ability of an antibody to cure prion-infected cells correlates with its binding affinity for PrP C rather than PrP Sc . We have visualized this interaction at the molecular level by determining the crystal structure of human PrP bound to the Fab fragment of monoclonal antibody ICSM 18, which has the highest affinity for PrP C and the highest therapeutic potency in vitro and in vivo. In this crystal structure, human PrP is observed in its native PrP C conformation. Interactions between neighboring PrP molecules in the crystal structure are mediated by close homotypic contacts between residues at position 129 that lead to the formation of a 4-strand intermolecular ␤-sheet. The importance of this residue in mediating protein-protein contact could explain the genetic susceptibility and prion strain selection determined by polymorphic residue 129 in human prion disease, one of the strongest common susceptibility polymorphisms known in any human disease.Creutzfeldt-Jakob disease ͉ PrP-Fab complex ͉ monoclonal antibody ͉ prion therapeutics

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...