Journal
NATURE
Volume 493, Issue 7430, Pages 111-+Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/nature11699
Keywords
-
Categories
Funding
- National Basic Research Program of China (973 Program) [2011CB910901, 2012CB910804, 2012CB917202]
- National Science Foundation of China [31070738]
- Chinese Academy of Sciences [KSCX2-EW-J-11]
- Shanghai Municipal Commission for Science and Technology [10PJ1411500]
- Young Talent Program of Shanghai Institutes for Biological Sciences, CAS [2010KIP101]
Ask authors/readers for more resources
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.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available