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.
Takamori
M
M
Department of Neurology, Kanazawa University School of Medicine, Japan.
Okumura
S
S
Komai
K
K
Satake
R
R
D000595:Amino Acid Sequence; D000818:Animals; D001327:Autoimmune Diseases / Q000276:immunology*; D002038:Bungarotoxins / Q000378:metabolism; D005260:Female; D007114:Immunization; D008969:Molecular Sequence Data; D009157:Myasthenia Gravis / Q000276:immunology*; D010446:Peptide Fragments / Q000138:chemical synthesis / Q000276:immunology*; D011487:Protein Conformation; D051381:Rats; D011917:Rats, Inbred Lew; D011950:Receptors, Cholinergic / Q000276:immunology / Q000378:metabolism; D011978:Receptors, Nicotinic / Q000235:genetics / Q000276:immunology*; D013329:Structure-Activity Relationship; D014101:Torpedo / Q000235:genetics; D064569:alpha7 Nicotinic Acetylcholine Receptor
D002038:Bungarotoxins; C579165:Chrna7 protein, rat; D010446:Peptide Fragments; D011950:Receptors, Cholinergic; D011978:Receptors, Nicotinic; D064569:alpha7 Nicotinic Acetylcholine Receptor