Structural insights into the molecular mechanisms of myasthenia gravis and their therapeutic implications
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 t...
Main Authors: | , , , , |
---|---|
Format: | Article |
Language: | English |
Published: |
eLife Sciences Publications Ltd
2017-04-01
|
Series: | eLife |
Subjects: | |
Online Access: | https://elifesciences.org/articles/23043 |
id |
doaj-dc254552d6ad4deabb5fc342005a6464 |
---|---|
record_format |
Article |
spelling |
doaj-dc254552d6ad4deabb5fc342005a64642021-05-05T13:26:00ZengeLife Sciences Publications LtdeLife2050-084X2017-04-01610.7554/eLife.23043Structural insights into the molecular mechanisms of myasthenia gravis and their therapeutic implicationsKaori Noridomi0https://orcid.org/0000-0002-4303-7511Go Watanabe1https://orcid.org/0000-0003-3911-3021Melissa N Hansen2Gye Won Han3Lin Chen4https://orcid.org/0000-0003-4798-6199Department of Chemistry, University of Southern California, Los Angeles, United StatesUSC Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, United StatesMolecular and Computational Biology, Department of Biological Sciences, University of Southern California, Los Angeles, United StatesDepartment of Chemistry, Bridge Institute, University of Southern California, Los Angeles, United StatesDepartment of Chemistry, University of Southern California, Los Angeles, United States; USC Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, United States; Molecular and Computational Biology, Department of Biological Sciences, University of Southern California, Los Angeles, United StatesThe 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.https://elifesciences.org/articles/23043myasthenia gravisnicotinic acetylcholine receptorscrystallographyautoantibodiesPichia pastoris |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Kaori Noridomi Go Watanabe Melissa N Hansen Gye Won Han Lin Chen |
spellingShingle |
Kaori Noridomi Go Watanabe Melissa N Hansen Gye Won Han Lin Chen Structural insights into the molecular mechanisms of myasthenia gravis and their therapeutic implications eLife myasthenia gravis nicotinic acetylcholine receptors crystallography autoantibodies Pichia pastoris |
author_facet |
Kaori Noridomi Go Watanabe Melissa N Hansen Gye Won Han Lin Chen |
author_sort |
Kaori Noridomi |
title |
Structural insights into the molecular mechanisms of myasthenia gravis and their therapeutic implications |
title_short |
Structural insights into the molecular mechanisms of myasthenia gravis and their therapeutic implications |
title_full |
Structural insights into the molecular mechanisms of myasthenia gravis and their therapeutic implications |
title_fullStr |
Structural insights into the molecular mechanisms of myasthenia gravis and their therapeutic implications |
title_full_unstemmed |
Structural insights into the molecular mechanisms of myasthenia gravis and their therapeutic implications |
title_sort |
structural insights into the molecular mechanisms of myasthenia gravis and their therapeutic implications |
publisher |
eLife Sciences Publications Ltd |
series |
eLife |
issn |
2050-084X |
publishDate |
2017-04-01 |
description |
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. |
topic |
myasthenia gravis nicotinic acetylcholine receptors crystallography autoantibodies Pichia pastoris |
url |
https://elifesciences.org/articles/23043 |
work_keys_str_mv |
AT kaorinoridomi structuralinsightsintothemolecularmechanismsofmyastheniagravisandtheirtherapeuticimplications AT gowatanabe structuralinsightsintothemolecularmechanismsofmyastheniagravisandtheirtherapeuticimplications AT melissanhansen structuralinsightsintothemolecularmechanismsofmyastheniagravisandtheirtherapeuticimplications AT gyewonhan structuralinsightsintothemolecularmechanismsofmyastheniagravisandtheirtherapeuticimplications AT linchen structuralinsightsintothemolecularmechanismsofmyastheniagravisandtheirtherapeuticimplications |
_version_ |
1721462048017088512 |