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A camelid antibody fragment inhibits the formation of amyloid fibrils by human lysozyme


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.

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Figure 1: Effect of cAb-HuL6 on the aggregation of D67H lysozyme.
Figure 2: Electrospray mass spectra of D67H lysozyme in the absence (a) and presence (b) of an equimolar amount of cAb-HuL6.
Figure 3: X-ray structure of wild-type human lysozyme complexed with cAb-HuL7.
Figure 4: Chemical shift perturbations induced by the binding of the cAb-HuL6 to wild-type lysozyme (a) and the D67H variant (b).


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The assistance of J. Zurdo, M. Krebs and B. Luisi for TEM and X-diffraction analysis of fibrils is gratefully acknowledged. We thank J.-M. Frère for many discussions. M.D. and D.C. were supported by a fellowship from the European Community. G.L. was supported by a fellowship from the Wenner-Gren Foundation. C.R. was supported by a BBSRC Advanced Research Fellowship. A.M. is a Research Associate of the FNRS, and was supported in part by a grant from the FRFC. C.V.R. is a Royal Society University Research Fellow. The research of C.M.D. is supported in part by a Programme Grant from the Wellcome Trust. This work was also supported by a BBSRC grant (to C.M.D., C.V.R. and D.B.A.) and by the Belgian Government through the PAI.

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Correspondence to Christopher M. Dobson.

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Dumoulin, M., Last, A., Desmyter, A. et al. A camelid antibody fragment inhibits the formation of amyloid fibrils by human lysozyme. Nature 424, 783–788 (2003).

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