Conformational modification enhances myasthenogenicity in synthetic peptide of acetylcholine receptor alpha-subunit.

The induction of myasthenia gravis depends on linked recognition of antigenic sites of acetylcholine receptor (AChR) by B-cells and T-cells. The former is conformationally restrained, and the latter is under the MHC class II restriction. We synthesized an artificially formed peptide (model peptide) by coupling the alpha 190-195 selected as B-cell site and cholinergic binding site and the alpha-107-116 selected as T-cell site and agretope with the intervening chain segment aligned as Asn-Pro-Gly-Gly (NPGG) to adopt beta-turn conformation. This model peptide, alpha 107-116-NPGG-alpha 190-195, was potently immunogenic in Lewis rats to provoke anti-peptide antibody reactive with native AChR and to induce the animal model of immunopharmacologic blockade of acetylcholine (ACh)-binding site. Low immunogenicity compared with this was found when using natural peptides predicted as sequences of B-cell site or T-cell site and the peptide synthesized by linking both without intervention of NPGG. The alpha 190-195 had no function of cholinergic binding either as a single segment or as part of the conformation-modified peptides; results suggest that the conformation modified for high immunogenicity does not assume the bioactive conformation for ACh-binding.