Impairment on the lateral mobility induced by structural changes underlies the functional deficiency of the lupus-associated polymorphism FcγRIIB-T232

• DOI: 10.1084/jem.20160528
• Publication Date: 2016-10-31T14:07:33Z
• Authors: Liling Xu; Mengdie Xia; Jun Guo; Xiaolin Sun; Hua Li; Chenguang Xu; Xiaomei Gu; Haowen Zhang; Junyang Yi; Yan Fang; Hengyi Xie; Jing Wang; Zhixun Shen; Boxin Xue; Yujie Sun; Tobias Meckel; Ying-Hua Chen; Zhibin Hu; Zhanguo Li; Chenqi Xu; Haipeng Gong; Wanli Liu
• Keywords: 0301 basic medicine; B-Lymphocytes; 0303 health sciences; Magnetic Resonance Spectroscopy; Cell Membrane; Receptors, IgG; Receptors, Antigen, B-Cell; Antigen-Antibody Complex; Molecular Dynamics Simulation; Models, Biological; Polymorphism, Single Nucleotide; Monocytes; Protein Structure, Secondary; Cell Line; 3. Good health; Diffusion; Membrane Lipids; 03 medical and health sciences; Humans; Lupus Erythematosus, Systemic; Amino Acid Sequence; Hydrophobic and Hydrophilic Interactions; Research Articles; Cells, Cultured; Fluorescence Recovery After Photobleaching

FcγRIIB functions to suppress the activation of immune cells. A single-nucleotide polymorphism in transmembrane (TM) domain FcγRIIB, FcγRIIB-T232, is associated with lupus. In this study, we investigated pathogenic mechanism FcγRIIB-T232 at both functional and structural levels. Our results showed that exhibited significantly reduced lateral mobility compared FcγRIIB-I232 was less enriched into microclusters complexes (ICs) after stimulation. However, if sufficient responding time given for diffuse interact ICs, can restore its inhibitory function. Moreover, substituting TM a fast floating CD86 molecule restored rapid function, which further corroborated importance Mechanistically, crippled be explained by changes domain. Both atomistic simulations nuclear magnetic resonance measurement indicated helix more inclined orientation than FcγRIIB-I232, thus resulting longer region embedded membrane. Therefore, conclude single-residue T232 enforces inclination thereby reduces FcγRIIB.