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.
Highlights
The nicotinic acetylcholine receptor at the neuromuscular junction (NMJ) is a ligand-gated ion channel that mediates rapid signal communication between spinal motor neurons and the muscle cells
Crystal structures of the antibody/receptor complexes mAb35 was chosen for structural analysis because it shares many functional characteristics with serum antibodies from myasthenia gravis (MG) patients and has been used as a reference MG antibody in extensive biochemical and functional studies (Tzartos et al, 1998, 1981)
MAb35 is derived from rat immunized with Electrophorus AChR, it competes with more than two thirds of serum antibodies from MG patients (Tzartos et al, 1982)
Summary
The nicotinic acetylcholine receptor (nAChR) at the neuromuscular junction (NMJ) is a ligand-gated ion channel that mediates rapid signal communication between spinal motor neurons and the muscle cells. This receptor is a major target of autoimmune antibodies in patients with myasthenia gravis (MG), an autoimmune disease that afflicts more than 20 in 100,000 people (Lindstrom, 2000; Vincent et al, 2001). The majority of MG cases can be diagnosed by the detection of autoantibodies to human muscle nAChR, and current treatment options include the use of acetylcholine esterase inhibitors, non-specific immunosuppressive drugs, plasmapheresis and thymectomy Most of these treatments are for symptomatic control except for thymectomy that may lead to disease remission. Other therapeutic approaches to treating MG, such as nAChR-specific immunosuppressive therapy (Luo and Lindstrom, 2015), need to be explored
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