The goal of this proposal is to study the binding, at the submolecular level, of autoantibodies and alpha-neurotoxin to human acetylcholine receptor (AChR). The extracellular part of the a chain of the human AChR will be synthesized in consecutive overlapping peptides of uniform size and overlaps and these peptides will be screened systematically for their ability to bend alpha-bungarotoxin BgTX and cobratoxin (CbTX). Similarly, the AChR-binding sites on BgTX will be localized by synthetic toxin peptides representing the various loops of BgTX as well as analogy based on consensus toxin structures. The orientation of the BgTX molecule in the AChR binding site will be determined by binding studies between the active peptides of AChR and the active peptides of the toxin. The AChR alpaha-chain peptides will be used to determine the specificity of the autoantibody responses in sera obtained from patients with Myasthenia Gravis. The work will provide a detailed understanding of the function of AChR and the changes in this function as a result of toxin or autoantibody binding.
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