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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS026280-02
Application #
3412000
Study Section
Neurological Sciences Subcommittee 1 (NLS)
Project Start
1989-04-01
Project End
1994-03-30
Budget Start
1990-04-01
Budget End
1991-03-31
Support Year
2
Fiscal Year
1990
Total Cost
Indirect Cost
Name
Baylor College of Medicine
Department
Type
Schools of Medicine
DUNS #
074615394
City
Houston
State
TX
Country
United States
Zip Code
77030
Oshima, M; Atassi, M Z (2000) T cells of mice treated with mPEG-myasthenogenic peptide conjugate are involved in protection against EAMG by stimulating lower pathogenic antibody responses. Autoimmunity 32:45-55
Rosenberg, J S; Atassi, M Z (1997) Intersite helper function of T cells specific for a protein epitope that is not recognized by antibodies. Immunol Invest 26:473-89
Atassi, M Z; Oshima, M (1997) Autoimmune responses against acetylcholine receptor: T and B cell collaboration and manipulation by synthetic peptides. Crit Rev Immunol 17:481-95
Rosenberg, J S; Oshima, M; Atassi, M Z (1996) B-cell activation in vitro by helper T cells specific to region alpha 146-162 of Torpedo californica nicotinic acetylcholine receptor. J Immunol 157:3192-9
Oshima, M; Atassi, M Z (1995) Effect of amino acid substitutions within the region 62-76 of I-A beta b on binding with and antigen presentation of Torpedo acetylcholine receptor alpha-chain peptide 146-162. J Immunol 154:5245-54
Atassi, M Z; Dolimbek, B Z; Manshouri, T (1995) Antibody and T-cell recognition of alpha-bungarotoxin and its synthetic loop-peptides. Mol Immunol 32:919-29
Christadoss, P; Shenoy, M; Oshima, M et al. (1994) Suppression of experimental autoimmune myasthenia gravis by epitope-specific neonatal tolerance. Adv Exp Med Biol 347:65-75
Jinnai, K; Ashizawa, T; Atassi, M S (1994) Analysis of exposed regions on the main extracellular domain of mouse acetylcholine receptor alpha subunit in live muscle cells by binding profiles of antipeptide antibodies. J Protein Chem 13:715-22
Atassi, M Z; Mulac-Jericevic, B (1994) Mapping the extracellular topography of the alpha-chain in free and in membrane-bound acetylcholine receptor by antibodies against overlapping peptides spanning the entire extracellular parts of the chain. J Protein Chem 13:37-47
Atassi, M Z; Mulac-Jericevic, B; Ashizawa, T (1994) Mapping of the polypeptide chain organization of the main extracellular domain of the alpha-subunit in membrane-bound acetylcholine receptor by antipeptide antibodies spanning the entire domain. Adv Exp Med Biol 347:221-8

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