Crystal structure of human prion protein bound to a therapeutic antibody

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 106; no. 8; pp. 2554 - 2558
• Main Authors: Antonyuk, S.V, Trevitt, C.R, Strange, R.W, Jackson, G.S, Sangar, D, Batchelor, M, Cooper, S, Fraser, C, Jones, S, Georgiou, T, Khalili-Shirazi, A, Clarke, A.R, Hasnain, S.S, Collinge, J
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 24.02.2009; National Acad Sciences
• Subjects: Antibodies; Antibodies, Monoclonal - metabolism; Biochemistry; Biological Sciences; Creutzfeldt Jakob syndrome; Creutzfeldt-Jakob disease; Crystal structure; Crystallography, X-Ray; Epitopes; Flow Cytometry; Humans; Immune system; Immunization; Immunoglobulin Fab Fragments - metabolism; Medical treatment; Models, Molecular; Molecules; Monoclonal antibodies; Polymorphism; Prion diseases; Prions; Prions - chemistry; Prions - metabolism; Protein Conformation
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.0809170106

Prion infection is characterized by the conversion of host cellular prion protein (PrPC) into disease-related conformers (PrPSc) 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 PrPC rather than PrPSc. 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 PrPC and the highest therapeutic potency in vitro and in vivo. In this crystal structure, human PrP is observed in its native PrPC 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 β-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.