Ca2+ regulates T-cell receptor activation by modulating the charge property of lipids

	Ca2+ regulates T-cell receptor activation by modulating the charge property of lipids
	Shi, XS; Bi, YC; Yang, W; Guo, XD; Jiang, Y; Wan, CJ; Li, LY; Bai, YB; Guo, J; Wang, YJ
刊名	NATURE
	2013
卷号	493 期号:7430 页码:111-111
通讯作者	Wang, JF (reprint author), Chinese Acad Sci, High Magnet Field Lab, Hefei Inst Phys Sci, 350 Shushanhu Rd, Hefei 230031, Anhui, Peoples R China.,junfeng@hmfl.ac.cn ; cqxu@sibcb.ac.cn
英文摘要	Ionic protein-lipid interactions are critical for the structure and function of membrane receptors, ion channels, integrins and many other proteins(1-7). However, the regulatory mechanism of these interactions is largely unknown. Here we show that Ca2+ can bind directly to anionic phospholipids and thus modulate membrane protein function. The activation of T-cell antigen receptor-CD3 complex (TCR), a key membrane receptor for adaptive immunity, is regulated by ionic interactions between positively charged CD3 epsilon/zeta cytoplasmic domains (CD3(CD)) and negatively charged phospholipids in the plasma membrane(1,8-10). Crucial tyrosines are buried in the membrane and are largely protected from phosphorylation in resting T cells. It is not clear how CD3CD dissociates from the membrane in antigen-stimulated T cells. The antigen engagement of even a single TCR triggers a Ca2+ influx(11) and TCR-proximal Ca2+ concentration is higher than the average cytosolic Ca2+ concentration(12). Our biochemical, live-cell fluorescence resonance energy transfer and NMR experiments showed that an increase in Ca2+ concentration induced the dissociation of CD3CD from the membrane and the solvent exposure of tyrosine residues. As a consequence, CD3 tyrosine phosphorylation was significantly enhanced by Ca2+ influx. Moreover, when compared with wild-type cells, Ca2+ channel-deficient T cells had substantially lower levels of CD3 phosphorylation after stimulation. The effect of Ca2+ on facilitating CD3 phosphorylation is primarily due to the charge of this ion, as demonstrated by the fact that replacing Ca2+ with the non-physiological ion Sr2+ resulted in the same feedback effect. Finally, P-31 NMR spectroscopy showed that Ca2+ bound to the phosphate group in anionic phospholipids at physiological concentrations, thus neutralizing the negative charge of phospholipids. Rather than initiating CD3 phosphorylation, this regulatory pathway of Ca2+ has a positive feedback effect on amplifying and sustaining CD3 phosphorylation and should enhance T-cell sensitivity to foreign antigens. Our study thus provides a new regulatory mechanism of Ca2+ to T-cell activation involving direct lipid manipulation.
学科主题	Science & Technology - Other Topics
类目[WOS]	Multidisciplinary Sciences
关键词[WOS]	IMMUNOLOGICAL SYNAPSE ; PLASMA-MEMBRANE ; CRAC CHANNEL ; K+ CHANNEL ; PROTEINS ; BINDING ; ORAI ; PHOSPHORYLATION ; RECOGNITION ; SIGNALS
收录类别	SCI
语种	英语
WOS记录号	WOS:000312933800041
内容类型	期刊论文
版本	出版稿
源URL	[http://202.127.25.143/handle/331003/481]
专题	上海生化细胞研究所_上海生科院生化细胞研究所
推荐引用方式 GB/T 7714	Shi, XS,Bi, YC,Yang, W,et al. Ca2+ regulates T-cell receptor activation by modulating the charge property of lipids[J]. NATURE,2013,493(7430):111-111.
APA	Shi, XS.,Bi, YC.,Yang, W.,Guo, XD.,Jiang, Y.,...&Xu, CQ.(2013).Ca2+ regulates T-cell receptor activation by modulating the charge property of lipids.NATURE,493(7430),111-111.
MLA	Shi, XS,et al."Ca2+ regulates T-cell receptor activation by modulating the charge property of lipids".NATURE 493.7430(2013):111-111.