Structural characterization of the main immunogenic region of the Torpedo acetylcholine receptor

Morell, Stuart W.; Trinh, Vu B.; Gudipati, Eswari; Friend, Alexander L.; Page, Nelson A.; Agius, Mark; Richman, David P.; Fairclough, Robert H.

doi:10.1016/j.molimm.2013.11.005

Cited by 3 publications

(13 citation statements)

References 29 publications

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“…Our structures reveal that the antibody-receptor binding interface indeed centers on the MIR and the N-terminal helix and also includes peripheral regions such as residues 15–23. Although the β5-β6-loop (residues 110–115) does not contact Fab35 in our structure, it may contribute to antibody binding indirectly by maintaining the natively folded structure of MIR (Morell et al, 2014). …”

Section: Discussionmentioning

confidence: 93%

“…Earlier studies mapped the core region of MIR to residues 67–76 (Barkas et al, 1988; Tzartos et al, 1988; Das and Lindstrom, 1989). More recent studies using natively folded nAChR α1/α7 chimera proteins (Luo et al, 2009) or GFP-fused protein fragments (Morell et al, 2014) showed that the N-terminal helix (residues 1–14) is also important for high-affinity MG antibody binding. These studies further indicated that other regions of nAChR, including the loop following helix 1 (residues 15–32) (Luo et al, 2009) and the β5-β6-loop packing against the MIR (residues 110–115) (Morell et al, 2014), also contribute to the binding of some MG antibodies.…”

Section: Discussionmentioning

confidence: 99%

“…More recent studies using natively folded nAChR α1/α7 chimera proteins (Luo et al, 2009) or GFP-fused protein fragments (Morell et al, 2014) showed that the N-terminal helix (residues 1–14) is also important for high-affinity MG antibody binding. These studies further indicated that other regions of nAChR, including the loop following helix 1 (residues 15–32) (Luo et al, 2009) and the β5-β6-loop packing against the MIR (residues 110–115) (Morell et al, 2014), also contribute to the binding of some MG antibodies. Our structures reveal that the antibody-receptor binding interface indeed centers on the MIR and the N-terminal helix and also includes peripheral regions such as residues 15–23.…”

Section: Discussionmentioning

confidence: 99%

“…Specific residues on MIR (Papadouli et al, 1990, 1993; Bellone et al, 1989) and the N-terminal helix (Morell et al, 2014) have also been analyzed using peptide/protein fragments containing mutations at specific positions for their roles on MG antibody binding. These studies showed that Asn68 and Asp71 of MIR are essential for MG antibody binding while the surrounding residues including Pro69 and Tyr72 showed partial effect when mutated.…”

Section: Discussionmentioning

confidence: 99%

“…Since then, extensive efforts have been put into characterizing the interactions between MG antibodies and nAChR using biochemical (Barkas et al, 1988; Tzartos et al, 1988; Das and Lindstrom, 1989; Saedi et al, 1990; Papadouli et al, 1990, 1993; Luo et al, 2009; Morell et al, 2014), structural (Dellisanti et al, 2007a; Beroukhim and Unwin, 1995; Kontou et al, 2000; Poulas et al, 2001), and modeling approaches (Kleinjung et al, 2000). These studies aimed to understand the basic mechanisms of MG and also the structure/function of nAChR in order to develop effective diagnosis and treatment for MG.…”

Section: Introductionmentioning

confidence: 99%

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

Noridomi

Watanabe

Hansen

et al. 2017

eLife

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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.DOI: http://dx.doi.org/10.7554/eLife.23043.001

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Section: Discussionmentioning

confidence: 93%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

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

Noridomi

Watanabe

Hansen

et al. 2017

eLife

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Targeting HIF-1α alleviates the inflammatory responses and rebuilds the CD4+ T cell subsets balance in the experimental autoimmune myasthenia gravis inflammation model via regulating cellular and humoral immunity

Yu,

Ran,

et al. 2024

Life Sciences

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Structure-Based Approaches to Antigen-Specific Therapy of Myasthenia Gravis

Xu¹,

Noridomi²,

Chen³

2019

Selected Topics in Myasthenia Gravis

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A majority of Myasthenia Gravis (MG) cases (~85%) are caused by pathological autoimmune antibodies to muscle nicotinic acetylcholine receptors (nAChRs). An attractive approach to treating MG is therefore blocking the binding of autoimmune antibodies to nAChR, or removing specifically nAChR antibodies, or selectively inhibiting and eliminating nAChR-specific B cells. This chapter will review highresolution structural studies of muscle nAChR and its complexes with antibodies derived from experimental autoimmune Myasthenia Gravis (EAMG). Based on these structural analyses, various strategies, including using small molecules to block the binding of MG autoimmune antibodies, and engineered chimeric nAChR antigen to specifically target and eliminate B cells that produce nAChR-specific antibodies, will be discussed.

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Structural characterization of the main immunogenic region of the Torpedo acetylcholine receptor

Cited by 3 publications

References 29 publications

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

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

Targeting HIF-1α alleviates the inflammatory responses and rebuilds the CD4+ T cell subsets balance in the experimental autoimmune myasthenia gravis inflammation model via regulating cellular and humoral immunity

Structure-Based Approaches to Antigen-Specific Therapy of Myasthenia Gravis

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