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

doi:10.1084/jem.20160528

	Impairment on the lateral mobility induced by structural changes underlies the functional deficiency of the lupus-associated polymorphism Fc gamma RIIB-T232
	Xu, Liling 1; Xia, Mengdie 2; Guo, Jun 3; Sun, Xiaolin 4; Li, Hua 3; Xu, Chenguang 1; Gu, Xiaomei 1; Zhang, Haowen 1; Yi, Junyang 1; Fang, Yan 1; Xie, Hengyi 1; Wang, Jing 1; Shen, Zhixun 1; Xue, Boxin 5; Sun, Yujie 5; Meckel, Tobias 6; Chen, Ying-Hua 1; Hu, Zhibin 7; Li, Zhanguo 4; Xu, Chenqi3,8 ; Gong, Haipeng 2; Liu, Wanli 1
	2016-11
发表期刊	JOURNAL OF EXPERIMENTAL MEDICINE
ISSN	0022-1007
卷号	213 期号:12 页码:2707-2727
发表状态	已发表
DOI	10.1084/jem.20160528
摘要	Fc gamma RIIB functions to suppress the activation of immune cells. A single-nucleotide polymorphism in the transmembrane (TM) domain of Fc gamma RIIB, Fc gamma RIIB-T232, is associated with lupus. In this study, we investigated the pathogenic mechanism of Fc gamma RIIB- T232 at both functional and structural levels. Our results showed that Fc gamma RIIB-T232 exhibited significantly reduced lateral mobility compared with Fc gamma RIIB-I232 and was significantly less enriched into the microclusters of immune complexes (ICs) after stimulation. However, if sufficient responding time is given for Fc gamma RIIB-T232 to diffuse and interact with the ICs, Fc gamma RIIB-T232 can restore its inhibitory function. Moreover, substituting the Fc gamma RIIB-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 Fc gamma RIIB to function. Mechanistically, the crippled lateral mobility of Fc gamma RIIB-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 Fc gamma RIIB-T232 exhibited a more inclined orientation than that of Fc gamma RIIB-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 Fc gamma RIIB.
收录类别	SCI
语种	英语
资助项目	MOST[2011CB910901] ; MOST[2012CB910804] ; MOST[2014CB541903]
WOS研究方向	Immunology ; Research & Experimental Medicine
WOS类目	Immunology ; Medicine, Research & Experimental
WOS记录号	WOS:000391122400013
出版者	ROCKEFELLER UNIV PRESS
WOS关键词	FC-GAMMA-RIIB ; B-CELL-RECEPTOR ; SINGLE-MOLECULE TRACKING ; PLASMA-MEMBRANE ; LIPID RAFTS ; ERYTHEMATOSUS ; PROTEIN ; SUSCEPTIBILITY ; DYNAMICS ; NMR
原始文献类型	Article
引用统计
文献类型	期刊论文
条目标识符	https://kms.shanghaitech.edu.cn/handle/2MSLDSTB/1652
专题	生命科学与技术学院_特聘教授组_许琛琦组
通讯作者	Li, Zhanguo; Xu, Chenqi; Gong, Haipeng; Liu, Wanli
作者单位	1.Tsinghua Univ, Minist Educ, Collaborat Innovat Ctr Diag & Treatment Infect Di, Key Lab Prot Sci,Inst Immunol, Beijing 100084, Peoples R China 2.Tsinghua Univ, Sch Life Sci, Key Lab Bioinformat, Minist Educ, Beijing 100084, Peoples R China 3.Chinese Acad Sci, Shanghai Inst Biol Sci, Inst Biochem & Cell Biol, State Key Lab Mol Biol,Natl Ctr Prot Sci Shanghai, Shanghai 200031, Peoples R China 4.Peking Univ, Dept Rheumatol & Immunol, Clin Immunol Ctr, Peoples Hosp, Beijing 100044, Peoples R China 5.Peking Univ, Sch Life Sci, Biodynam Opt Imaging Ctr, State Key Lab Biomembrane & Membrane Biotechnol, Beijing 100871, Peoples R China 6.Tech Univ Darmstadt, Dept Biol, Membrane Dynam, D-64287 Darmstadt, Germany 7.Nanjing Med Univ, Sch Publ Hlth, Dept Epidemiol, Nanjing 211166, Jiangsu, Peoples R China 8.ShanghaiTech Univ, Sch Life Sci & Technol, Shanghai 200031, Peoples R China
通讯作者单位	生命科学与技术学院
推荐引用方式 GB/T 7714	Xu, Liling,Xia, Mengdie,Guo, Jun,et al. Impairment on the lateral mobility induced by structural changes underlies the functional deficiency of the lupus-associated polymorphism Fc gamma RIIB-T232[J]. JOURNAL OF EXPERIMENTAL MEDICINE,2016,213(12):2707-2727.
APA	Xu, Liling.,Xia, Mengdie.,Guo, Jun.,Sun, Xiaolin.,Li, Hua.,...&Liu, Wanli.(2016).Impairment on the lateral mobility induced by structural changes underlies the functional deficiency of the lupus-associated polymorphism Fc gamma RIIB-T232.JOURNAL OF EXPERIMENTAL MEDICINE,213(12),2707-2727.
MLA	Xu, Liling,et al."Impairment on the lateral mobility induced by structural changes underlies the functional deficiency of the lupus-associated polymorphism Fc gamma RIIB-T232".JOURNAL OF EXPERIMENTAL MEDICINE 213.12(2016):2707-2727.