Structural basis of amyloid fibril recognition by a conformation-sensitive antibody domain
Final Report Abstract
Alzheimer’s disease (AD) is associated with the self-assembly of β-amyloid (Aβ) peptide into highly structured aggregates, termed amyloid fibrils. Conformation-specific antibodies that target such protein aggregates may be an invaluable tool in amyloid research as well as a promising therapeutic strategy. The Fändrich group has previously obtained recombinant antibody domains which bind in a conformation-dependent manner to amyloid structures, including fibrils or oligomers. This included the antibody fragment B10 which was previously found to bind Aβ specifically to Aβ fibrils and not monomeric peptide or oligomeric intermediates. Within this project we proposed to characterize B10 and the molecular basis of its conformation-specificity towards Aβ amyloid fibrils. Using immunostaining techniques, mutagenesis and X-ray crystallography we found that B10 interacts with different fibrillar structures mainly through cationic interactions. Fibril conformation-specificity may depend upon specific electrostatic interactions with an acidic moiety, which is common to different amyloid fibrils, resembling a pattern recognition mechanism. B10 further allowed the stabilization of Aβ protofibrils, intermediate species on the process of fibril formation. NMR studies revealed the structural resemblance of protofibrils and fibrils and illuminated structural remodelling processes occurring during fibril formation. Additional studies with an oligomer specific antibody fragment revealed that fibrils and oligomers are recognized through very different mechanisms. Our results contributed to the understanding of how disease-related amyloid structures can be recognized by ligands and provided structural information on the process of amyloid aggregation. These findings can be generally relevant for applications of amyloid-specific binders such as amyloid disease diagnosis, prospective therapeutic approaches as well as a better understanding of the amyloid aggregation process.
Publications
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2011. Amyloid fibril recognition with the conformational B10 antibody fragment depends on electrostatic interactions. Journal of Molecular Biology. 405, 341-348
Haupt, C., Morgado, I., Kumar, S. T., Parthier, C., Bereza, M., Hortschansky, P., Stubbs M. T., Horn, U., Fändrich, M.
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2011. Dynamics of Amyloid β Fibrils Revealed by Solid-State NMR. Journal of Biological Chemistry. 287, 2017-2021
Scheidt, H., Morgado, I., Rothemund, S., Huster D.
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2011. Solid-State NMR Spectroscopic investigation of Aβ protofibrils: implication of a β-sheet remodeling upon maturation into terminal amyloid fibrils. Angewandte Chemie International Edition. 50, 2837-2840
Scheidt, H., Morgado, I., Rothemund, S., Huster D., Fändrich, M.
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Assembly of Alzheimer's Aβ peptide into nanostructured amyloid fibrils. 2011. Current Opinion in Colloid & Interface Science. 16, 508-514
Morgado, I., Fändrich, M.
