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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...

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Detalles Bibliográficos
Autores principales: Hu, Wei, Zhang, Yong, Sun, Xiaolin, Zhang, Tongtong, Xu, Liling, Xie, Hengyi, Li, Zhanguo, Liu, Wanli, Lou, Jizhong, Chen, Wei
Formato: Online Artículo Texto
Lenguaje:English
Publicado: eLife Sciences Publications, Ltd 2019
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.
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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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