Abstract
The reactivity of amyloid-oligomer specific antibody, A11, towards soluble oligomer aggregates formed by proteins with varying sequences suggests that it recognizes a generic, sequence independent epitope that is shared among these soluble oligomers. This epitope appears to be associated with soluble amyloid oligomers and not with amyloid fibrils or natively-folded proteins. Currently, the detailed structure of the soluble oligomers of amyloid beta (Aβ) peptides and other amyloid-related proteins and the epitope or structural motif on soluble oligomers that these conformation-specific antibodies recognize are unknown. Co-crystallization of oligomers in complex with the antigen-binding fragments (Fab) of oligomer-specific antibodies may be a promising approach to study the structure of these oligomers due to the binding specificity of antibodies to their antigen and the crystallizability of the antigen-binding fragments (Fab) of antibodies. 48, 55, 204, and 205 (subtypes of A11) are rabbit monoclonal immunoglobulin Gs (IgGs) that show reactivity for generic oligomer epitopes. Here, the x-ray structure of 204Fab at 1.6 A resolution is reported. The structure of the apo complementarity-determining regions (CDR) of 204Fab may provide insights into how this conformation-specific antibody recognizes Aβ oligomers. This is also the first reported structure of a rabbit Fab, and it reveals a novel interdomain disulfide bond. Crystallization trials of the Fab and ScFV (Single-chain Variable Fragments) of other oligomer-specific monoclonal antibodies and the co-crystals with oligomers are under way. If co-crystallization of the complex made of the amyloid oligomer and oligomer-specific antibodies are successful, the structural information gained from these studies may contribute to the greater understanding of the molecular mechanism of the toxicity associated with the soluble oligomers. Supported by NIH AG00538, the Cure Alzheimer Fund and a grant from the Larry L. Hillblom Foundation.
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