Crystal structure of human prion protein bound to a therapeutic antibody

Abstract

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

Molecular Dynamics as an Approach to Study Prion Protein Misfolding and the Effect of Pathogenic Mutations

“…For PrP, the first [8] and most abundant structural information has been obtained by nuclear magnetic resonance techniques (NMR), which has resulted in experimentally derived models of PrP of a wide variety of species [64][65][66][67][68][69][70]. For human and sheep PrP, structures determined by X-ray crystallography have also been reported, both with and without antibodies bound [71][72][73][74][75]. The overall structure of PrP that has emerged from these studies is largely identical for the different species and conditions.…”

Conservation of a Glycine-rich Region in the Prion Protein Is Required for Uptake of Prion Infectivity

“…This ␤-sheet is known to undergo slow conformational flexing when analyzed by NMR (49), and molecular dynamics simulations have indicated the transient formation of extended ␤-sheet structures that can incorporate the entire GRR glycines as either ␤-strand or inter-strand turns (50,51). Crystal structures of PrP demonstrate a PrP-PrP dimer that involves the formations of an interprotein ␤-sheet (52,53). These results suggest that an initial step in the formation of PrP Sc involves formation of a ␤-sheet within this area.…”

Pharmacological chaperone for the structured domain of human prion protein

“…The fact that the biological role of PrP remains unclear (23) precludes the use of screens for compounds that alter its activity. The recently reported crystal structure of human PrP C (24) and also the NMR structures of human PrP C show no obvious clefts for ligand binding (21). In contrast, a number of molecules have been demonstrated to bind to the unstructured region of PrP including pentosan polysulfate (25), Congo red (26), and a number of anionic tetrapyrroles (27,28).…”