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FcγRIIB-I232T polymorphic change allosterically suppresses ligand binding
FcγRIIB binding to its ligand suppresses immune cell activation. A single-nucleotide polymorphic (SNP) change, I232T, in the transmembrane (TM) domain of FcγRIIB loses its suppressive function, which is clinically associated with systemic lupus erythematosus (SLE). Previously, we reported that I232T...
Autores principales: | , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
eLife Sciences Publications, Ltd
2019
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6711707/ https://www.ncbi.nlm.nih.gov/pubmed/31343409 http://dx.doi.org/10.7554/eLife.46689 |
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author | Hu, Wei Zhang, Yong Sun, Xiaolin Zhang, Tongtong Xu, Liling Xie, Hengyi Li, Zhanguo Liu, Wanli Lou, Jizhong Chen, Wei |
author_facet | Hu, Wei Zhang, Yong Sun, Xiaolin Zhang, Tongtong Xu, Liling Xie, Hengyi Li, Zhanguo Liu, Wanli Lou, Jizhong Chen, Wei |
author_sort | Hu, Wei |
collection | PubMed |
description | FcγRIIB binding to its ligand suppresses immune cell activation. A single-nucleotide polymorphic (SNP) change, I232T, in the transmembrane (TM) domain of FcγRIIB loses its suppressive function, which is clinically associated with systemic lupus erythematosus (SLE). Previously, we reported that I232T tilts FcγRIIB’s TM domain. In this study, combining with molecular dynamics simulations and single-cell FRET assay, we further reveal that such tilting by I232T unexpectedly bends the FcγRIIB’s ectodomain toward plasma membrane to allosterically impede FcγRIIB’s ligand association. I232T substitution reduces in situ two-dimensional binding affinities and association rates of FcγRIIB to interact with its ligands, IgG1, IgG2 and IgG3 by three to four folds. This allosteric regulation by an SNP provides an intrinsic molecular mechanism for the functional loss of FcγRIIB-I232T in SLE patients. |
format | Online Article Text |
id | pubmed-6711707 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | eLife Sciences Publications, Ltd |
record_format | MEDLINE/PubMed |
spelling | pubmed-67117072019-08-30 FcγRIIB-I232T polymorphic change allosterically suppresses ligand binding Hu, Wei Zhang, Yong Sun, Xiaolin Zhang, Tongtong Xu, Liling Xie, Hengyi Li, Zhanguo Liu, Wanli Lou, Jizhong Chen, Wei eLife Immunology and Inflammation FcγRIIB binding to its ligand suppresses immune cell activation. A single-nucleotide polymorphic (SNP) change, I232T, in the transmembrane (TM) domain of FcγRIIB loses its suppressive function, which is clinically associated with systemic lupus erythematosus (SLE). Previously, we reported that I232T tilts FcγRIIB’s TM domain. In this study, combining with molecular dynamics simulations and single-cell FRET assay, we further reveal that such tilting by I232T unexpectedly bends the FcγRIIB’s ectodomain toward plasma membrane to allosterically impede FcγRIIB’s ligand association. I232T substitution reduces in situ two-dimensional binding affinities and association rates of FcγRIIB to interact with its ligands, IgG1, IgG2 and IgG3 by three to four folds. This allosteric regulation by an SNP provides an intrinsic molecular mechanism for the functional loss of FcγRIIB-I232T in SLE patients. eLife Sciences Publications, Ltd 2019-07-25 /pmc/articles/PMC6711707/ /pubmed/31343409 http://dx.doi.org/10.7554/eLife.46689 Text en © 2019, Hu et al http://creativecommons.org/licenses/by/4.0/ http://creativecommons.org/licenses/by/4.0/This article is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use and redistribution provided that the original author and source are credited. |
spellingShingle | Immunology and Inflammation Hu, Wei Zhang, Yong Sun, Xiaolin Zhang, Tongtong Xu, Liling Xie, Hengyi Li, Zhanguo Liu, Wanli Lou, Jizhong Chen, Wei FcγRIIB-I232T polymorphic change allosterically suppresses ligand binding |
title | FcγRIIB-I232T polymorphic change allosterically suppresses ligand binding |
title_full | FcγRIIB-I232T polymorphic change allosterically suppresses ligand binding |
title_fullStr | FcγRIIB-I232T polymorphic change allosterically suppresses ligand binding |
title_full_unstemmed | FcγRIIB-I232T polymorphic change allosterically suppresses ligand binding |
title_short | FcγRIIB-I232T polymorphic change allosterically suppresses ligand binding |
title_sort | fcγriib-i232t polymorphic change allosterically suppresses ligand binding |
topic | Immunology and Inflammation |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6711707/ https://www.ncbi.nlm.nih.gov/pubmed/31343409 http://dx.doi.org/10.7554/eLife.46689 |
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