Structural basis of amyloid fibril recognition by a conformation-sensitive antibody domain

• Applicant: Dr. Isabel Morgado
• Subject Area: Structural Biology
• Term: from 2009 to 2011
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 128368446

Many different protein sequences can misfold into disease-associated amyloid fibrils that share a common but not fully understood structure. A promising tool in amyloid research is the generation of antibodies that recognize amyloid fibrils by their specific conformation. The Fandrich lab has previously obtained a recombinant antibody domain, termed B10, which binds in a conformation-dependent manner to different amyloid fibrils, such as fibrils derived from Alzheimer’s Aβ peptide or serum amyloid A protein. Furthermore, B10 prevents mature fibril formation by stabilizing Aβ protofibrils, the structural precursors of mature amyloid fibrils. I here propose to assess the molecular basis by which B10 is able to bind to a common epitope of different amyloid fibrils. The work will involve in-detail assessment of the B10 specificity with differently structured Aβ aggregates and amyloid fibrils from different polypeptide sequences, site-directed mutagenesis of complementarity determining regions of B10, X-ray crystallography and other biochemical methods. These studies aim to provide information about the binding of conformation-sensitive antibodies and the molecular structure of amyloid fibrils. Such data is relevant for further applications of conformation-sensitive antibodies in basic research, medical diagnosis or therapy.

• DFG Programme: Research Grants