FcγRIIB-I232T polymorphic change allosterically suppresses ligand binding
- Zhejiang University School of Medicine, China
- Institute of Biophysics, Chinese Academy of Sciences, China
- Peking University People's Hospital, China
- Tsinghua University, China
Abstract
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 tilted 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 towards 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 a SNP provides an intrinsic molecular mechanism for the functional loss of FcγRIIB-I232T in SLE patients.
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All data generated or analysed during this study are included in the manuscript and supporting files.
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Funding
Natural Basic Research Program of China (2015CB910800)
- Wei Chen
Natural Science Foundation of China (31470900)
- Wei Chen
Natural Science Foundation of China (31522021)
- Wei Chen
Natural Science Foundation of China (11672317)
- Jizhong Lou
Natural Science Foundation of China (11772348)
- Yong Zhang
Fundamental Research Founds for the Central Universities (2015XZZX004-32)
- Wei Chen
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Human subjects: The ethics committee of Peking University People's Hospital approved this study and informed consents were obtained from each patient and healthy volunteer. All the human cell associated experimental guidelines were approved by the Medical Ethics Committee of Peking University People's Hospital (approval no. 2014PHB116-01) and by the Medical Ethics Committee of Tsinghua University (approval no. 20180029).
Copyright
© 2019, Hu et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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FcγRIIB-I232T polymorphic change allosterically suppresses ligand binding
eLife 8:e46689.
https://doi.org/10.7554/eLife.46689
