Letters to Nature
Nature 424, 783-788 (14 August 2003) | doi:10.1038/nature01870; Received 22 March 2003; Accepted 18 June 2003
A camelid antibody fragment inhibits the formation of amyloid fibrils by human lysozyme
Mireille Dumoulin1, Alexander M. Last2, Aline Desmyter3,8, Klaas Decanniere3, Denis Canet2,8, Göran Larsson1, Andrew Spencer4, David B. Archer5, Jurgen Sasse6, Serge Muyldermans3, Lode Wyns3, Christina Redfield2, André Matagne7, Carol V. Robinson1 & Christopher M. Dobson1
- Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, UK
- Oxford Centre for Molecular Sciences, University of Oxford, South Parks Road, Oxford OX1 3QH, UK
- Department Ultrastructure, Vrije Universiteit Brussel, Pleinlaan 2, B-1050 Brussels, Belgium
- Institute of Food Research, Norwich Research Park, Colney, Norwich NR4 7UA, UK
- School of Life and Environmental Sciences, University of Nottingham, University Park, Nottingham NG7 2RD, UK
- Central Veterinary Research Laboratory, P.O. Box 597, Dubai, United Arab Emirates
- Laboratoire d'Enzymologie, Centre d'Ingénerie des Protéines, Institut de Chimie B6, Université de Liège, B-4000 Liège (Sart Tilman), Belgium
- Present addresses: Centre National de la Recherche Scientifique, 31 Chemin Joseph Aiguier, 13402 Marseille, France (A.D.); Gene Prot Inc., 2 Pré-de-la-Fontaine, 1217 Meyrin/GE, Switzerland (D.C.)
Correspondence to: Christopher M. Dobson1 Email: cmd44@cam.ac.uk
Amyloid diseases are characterized by an aberrant assembly of a specific protein or protein fragment into fibrils and plaques that are deposited in various organs and tissues1, 2, 3, often with serious pathological consequences. Non-neuropathic systemic amyloidosis4, 5, 6 is associated with single point mutations in the gene coding for human lysozyme. Here we report that a single-domain fragment of a camelid antibody7, 8, 9 raised against wild-type human lysozyme inhibits the in vitro aggregation of its amyloidogenic variant, D67H. Our structural studies reveal that the epitope includes neither the site of mutation nor most residues in the region of the protein structure that is destabilized by the mutation. Instead, the binding of the antibody fragment achieves its effect by restoring the structural cooperativity characteristic of the wild-type protein. This appears to occur at least in part through the transmission of long-range conformational effects to the interface between the two structural domains of the protein. Thus, reducing the ability of an amyloidogenic protein to form partly unfolded species can be an effective method of preventing its aggregation, suggesting approaches to the rational design of therapeutic agents directed against protein deposition diseases.
