title: Impairment on the lateral mobility induced by structural changes underlies the functional deficiency of the lupus-associated polymorphism FcγRIIB-T232.
abstract: FcγRIIB functions to suppress the activation of immune cells. A single-nucleotide polymorphism in the transmembrane (TM) domain of FcγRIIB, FcγRIIB-T232, is associated with lupus. In this study, we investigated the pathogenic mechanism of FcγRIIB-T232 at both functional and structural levels. Our results showed that FcγRIIB-T232 exhibited significantly reduced lateral mobility compared with FcγRIIB-I232 and was significantly less enriched into the microclusters of immune complexes (ICs) after stimulation. However, if sufficient responding time is given for FcγRIIB-T232 to diffuse and interact with the ICs, FcγRIIB-T232 can restore its inhibitory function. Moreover, substituting the FcγRIIB-T232 TM domain with that of a fast floating CD86 molecule restored both the rapid mobility and the inhibitory function, which further corroborated the importance of fast mobility for FcγRIIB to function. Mechanistically, the crippled lateral mobility of FcγRIIB-T232 can be explained by the structural changes of the TM domain. Both atomistic simulations and nuclear magnetic resonance measurement indicated that the TM helix of FcγRIIB-T232 exhibited a more inclined orientation than that of FcγRIIB-I232, thus resulting in a longer region embedded in the membrane. Therefore, we conclude that the single-residue polymorphism T232 enforces the inclination of the TM domain and thereby reduces the lateral mobility and inhibitory functions of FcγRIIB.
authors: Ministry of Education Key Laboratory of Protein Sciences, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Institute for Immunology, School of Life Sciences, Tsinghua University, Beijing 100084, China.
authors: Liling
authors: L
authors: Xu
authors: Ministry of Education Key Laboratory of Bioinformatics, School of Life Sciences, Tsinghua University, Beijing 100084, China.
authors: Mengdie
authors: M
authors: Xia
authors: National Center for Protein Science Shanghai, State Key Laboratory of Molecular Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
authors: Jun
authors: 0000-0002-9403-5305
authors: J
authors: Guo
authors: Department of Rheumatology and Immunology, Clinical Immunology Center, Peking University People's Hospital, Beijing 100044, China.
authors: Xiaolin
authors: X
authors: Sun
authors: National Center for Protein Science Shanghai, State Key Laboratory of Molecular Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
authors: Hua
authors: H
authors: Li
authors: Ministry of Education Key Laboratory of Protein Sciences, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Institute for Immunology, School of Life Sciences, Tsinghua University, Beijing 100084, China.
authors: Chenguang
authors: 0000-0003-3650-9506
authors: C
authors: Xu
authors: Ministry of Education Key Laboratory of Protein Sciences, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Institute for Immunology, School of Life Sciences, Tsinghua University, Beijing 100084, China.
authors: Xiaomei
authors: X
authors: Gu
authors: Ministry of Education Key Laboratory of Protein Sciences, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Institute for Immunology, School of Life Sciences, Tsinghua University, Beijing 100084, China.
authors: Haowen
authors: H
authors: Zhang
authors: Ministry of Education Key Laboratory of Protein Sciences, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Institute for Immunology, School of Life Sciences, Tsinghua University, Beijing 100084, China.
authors: Junyang
authors: J
authors: Yi
authors: Ministry of Education Key Laboratory of Protein Sciences, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Institute for Immunology, School of Life Sciences, Tsinghua University, Beijing 100084, China.
authors: Yan
authors: Y
authors: Fang
authors: Ministry of Education Key Laboratory of Protein Sciences, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Institute for Immunology, School of Life Sciences, Tsinghua University, Beijing 100084, China.
authors: Hengyi
authors: H
authors: Xie
authors: Ministry of Education Key Laboratory of Protein Sciences, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Institute for Immunology, School of Life Sciences, Tsinghua University, Beijing 100084, China.
authors: Jing
authors: J
authors: Wang
authors: Ministry of Education Key Laboratory of Protein Sciences, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Institute for Immunology, School of Life Sciences, Tsinghua University, Beijing 100084, China.
authors: Zhixun
authors: Z
authors: Shen
authors: State Key Laboratory of Biomembrane and Membrane Biotechnology, Biodynamic Optical Imaging Center, School of Life Sciences, Peking University, Beijing 100871, China.
authors: Boxin
authors: B
authors: Xue
authors: State Key Laboratory of Biomembrane and Membrane Biotechnology, Biodynamic Optical Imaging Center, School of Life Sciences, Peking University, Beijing 100871, China.
authors: Yujie
authors: Y
authors: Sun
authors: Membrane Dynamics, Department of Biology, Technische Universität Darmstadt, 64287 Darmstadt, Germany.
authors: Tobias
authors: 0000-0003-0759-2072
authors: T
authors: Meckel
authors: Ministry of Education Key Laboratory of Protein Sciences, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Institute for Immunology, School of Life Sciences, Tsinghua University, Beijing 100084, China.
authors: Ying-Hua
authors: YH
authors: Chen
authors: Department of Epidemiology, School of Public Health, Nanjing Medical University, Nanjing 211166, China.
authors: Zhibin
authors: Z
authors: Hu
authors: Department of Rheumatology and Immunology, Clinical Immunology Center, Peking University People's Hospital, Beijing 100044, China liulab@tsinghua.edu.cn li99@bjmu.edu.cn cqxu@sibcb.ac.cn hgong@tsinghua.edu.cn.
authors: Zhanguo
authors: Z
authors: Li
authors: National Center for Protein Science Shanghai, State Key Laboratory of Molecular Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China liulab@tsinghua.edu.cn li99@bjmu.edu.cn cqxu@sibcb.ac.cn hgong@tsinghua.edu.cn.|School of Life Science and Technology, ShanghaiTech University, Shanghai 200031, China.
authors: Chenqi
authors: C
authors: Xu
authors: Ministry of Education Key Laboratory of Bioinformatics, School of Life Sciences, Tsinghua University, Beijing 100084, China liulab@tsinghua.edu.cn li99@bjmu.edu.cn cqxu@sibcb.ac.cn hgong@tsinghua.edu.cn.
authors: Haipeng
authors: 0000-0002-5532-1640
authors: H
authors: Gong
authors: Ministry of Education Key Laboratory of Protein Sciences, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Institute for Immunology, School of Life Sciences, Tsinghua University, Beijing 100084, China liulab@tsinghua.edu.cn li99@bjmu.edu.cn cqxu@sibcb.ac.cn hgong@tsinghua.edu.cn.
authors: Wanli
authors: W
authors: Liu
mesh_terms: D000595:Amino Acid Sequence; D000936:Antigen-Antibody Complex / Q000378:metabolism; D001402:B-Lymphocytes / Q000378:metabolism; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism; D002478:Cells, Cultured; D004058:Diffusion; D036681:Fluorescence Recovery After Photobleaching; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D008180:Lupus Erythematosus, Systemic / Q000235:genetics*; D009682:Magnetic Resonance Spectroscopy; D008563:Membrane Lipids / Q000378:metabolism; D008954:Models, Biological; D056004:Molecular Dynamics Simulation; D009000:Monocytes / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D017433:Protein Structure, Secondary; D011947:Receptors, Antigen, B-Cell / Q000378:metabolism; D017452:Receptors, IgG / Q000737:chemistry* / Q000235:genetics* / Q000378:metabolism; D000072760:Single Molecule Imaging
chemical_list: D000936:Antigen-Antibody Complex; C499173:FCGR2B protein, human; D008563:Membrane Lipids; D011947:Receptors, Antigen, B-Cell; D017452:Receptors, IgG