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Fc?RIIB-I232T polymorphic change allosterically suppresses ligand binding.

ABSTRACT: Fc?RIIB binding to its ligand suppresses immune cell activation. A single-nucleotide polymorphic (SNP) change, I232T, in the transmembrane (TM) domain of Fc?RIIB loses its suppressive function, which is clinically associated with systemic lupus erythematosus (SLE). Previously, we reported that I232T tilts Fc?RIIB'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 Fc?RIIB's ectodomain toward plasma membrane to allosterically impede Fc?RIIB's ligand association. I232T substitution reduces in situ two-dimensional binding affinities and association rates of Fc?RIIB 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 Fc?RIIB-I232T in SLE patients.

SUBMITTER: Hu W

PROVIDER: S-EPMC6711707 | biostudies-literature | 2019 Jul

REPOSITORIES: biostudies-literature

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FcγRIIB-I232T polymorphic change allosterically suppresses ligand binding.

Hu Wei W Zhang Yong Y Sun Xiaolin X Zhang Tongtong T Xu Liling L Xie Hengyi H Li Zhanguo Z Liu Wanli W Lou Jizhong J Chen Wei W

eLife 20190725

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 ectod ...[more]

PMID: 31343409

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