Structural insights into the molecular mechanisms of myasthenia gravis and their therapeutic implications

Author:

Noridomi Kaori1ORCID,Watanabe Go2ORCID,Hansen Melissa N3,Han Gye Won4,Chen Lin123ORCID

Affiliation:

1. Department of Chemistry, University of Southern California, Los Angeles, United States

2. USC Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, United States

3. Molecular and Computational Biology, Department of Biological Sciences, University of Southern California, Los Angeles, United States

4. Department of Chemistry, Bridge Institute, University of Southern California, Los Angeles, United States

Abstract

The nicotinic acetylcholine receptor (nAChR) is a major target of autoantibodies in myasthenia gravis (MG), an autoimmune disease that causes neuromuscular transmission dysfunction. Despite decades of research, the molecular mechanisms underlying MG have not been fully elucidated. Here, we present the crystal structure of the nAChR α1 subunit bound by the Fab fragment of mAb35, a reference monoclonal antibody that causes experimental MG and competes with ~65% of antibodies from MG patients. Our structures reveal for the first time the detailed molecular interactions between MG antibodies and a core region on nAChR α1. These structures suggest a major nAChR-binding mechanism shared by a large number of MG antibodies and the possibility to treat MG by blocking this binding mechanism. Structure-based modeling also provides insights into antibody-mediated nAChR cross-linking known to cause receptor degradation. Our studies establish a structural basis for further mechanistic studies and therapeutic development of MG.

Funder

National Institutes of Health

Publisher

eLife Sciences Publications, Ltd

Subject

General Immunology and Microbiology,General Biochemistry, Genetics and Molecular Biology,General Medicine,General Neuroscience

Reference62 articles.

1. Monoclonal antibodies to the main immunogenic region of the nicotinic acetylcholine receptor bind to residues 61-76 of the alpha subunit;Barkas;The Journal of Biological Chemistry,1988

2. The main immunogenic region of the nicotinic acetylcholine receptor. identification of amino acid residues interacting with different antibodies;Bellone;Journal of Immunology,1989

3. Three-dimensional location of the main immunogenic region of the acetylcholine receptor;Beroukhim;Neuron,1995

4. Myasthenia gravis, a model of organ-specific autoimmune disease;Berrih-Aknin;Journal of Autoimmunity,1995

5. In pursuit of the high-resolution structure of nicotinic acetylcholine receptors;Chen;The Journal of Physiology,2010

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