A novel EF-hand protein, CRACR2A, is a cytosolic Ca2+ sensor that stabilizes CRAC channels in T cells.
A novel EF-hand protein, CRACR2A, is a cytosolic Ca2+ sensor that stabilizes CRAC channels in T cells.
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DOI：
10.1038/ncb2045
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发表时间：
2010-05
影响因子：
21.3
通讯作者：
Gwack, Yousang
中科院分区：
文献类型：
--
作者：
Srikanth, Sonal;Jung, Hea-Jin;Kim, Kyun-Do;Souda, Puneet;Whitelegge, Julian;Gwack, Yousang
ORAI1和STIM1是钙释放激活的钙通道(CRAC)的重要组成部分，它介导免疫细胞内的钙库操纵性钙内流(SOCE)。虽然Orai1和STIM1共同聚集和物理上相互作用来调节SOCE，但调控这些功能的细胞质机制仍然知之甚少。我们利用亲和蛋白纯化的方法寻找Orai1和STIM1的调节剂，并鉴定了一个新的EF-Hand蛋白CRACR2A(CRAC调节器2A，EFCAB4B，FLJ33805)。我们发现CRACR2A直接与Orai1和STIM1相互作用，形成一个三元复合体，在升高的钙离子浓度下解离。利用siRNA介导的敲除和突变的研究表明，CRACR2A对于Orai1和STIM1在储备耗尽时的聚集是重要的。CRACR2A的EF-Hand突变体的表达促进了STIM1的聚集，提高了细胞质钙离子水平，并诱导了细胞死亡，表明它与CRAC通道有积极的相互作用。这些观察结果表明，CRACR2A是一种新的钙结合蛋白，在T细胞中高表达，在脊椎动物中保守，是CRAC通道介导的SOCE的关键调节因子。
Orai1 and STIM1 are critical components of Ca2+ release-activated Ca2+ (CRAC) channels that mediate store-operated Ca2+ entry (SOCE) in immune cells. While Orai1 and STIM1 co-cluster and physically interact to mediate SOCE, the cytoplasmic machinery modulating these functions remains poorly understood. We sought to find modulators of Orai1 and STIM1 using affinity protein purification and identified a novel EF-hand protein, CRACR2A (CRAC regulator 2A, EFCAB4B, FLJ33805). We show that CRACR2A directly interacts with Orai1 and STIM1, forming a ternary complex that dissociates at elevated Ca2+ concentrations. Studies using siRNA-mediated knockdown and mutagenesis show that CRACR2A is important for clustering of Orai1 and STIM1 upon store depletion. Expression of an EF-hand mutant of CRACR2A enhanced STIM1 clustering, elevated cytoplasmic Ca2+ and induced cell death, suggesting its active interaction with CRAC channels. These observations implicate CRACR2A, a novel Ca2+ binding protein, highly expressed in T cells and conserved in vertebrates, as a key regulator of CRAC channel-mediated SOCE.
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影响因子：
64.5
作者：
Park CY;Hoover PJ;Mullins FM;Bachhawat P;Covington ED;Raunser S;Walz T;Garcia KC;Dolmetsch RE;Lewis RS
通讯作者：
Lewis RS
影响因子：
2.7
作者：
MARUYAMA, K;MIKAWA, T;EBASHI, S
通讯作者：
EBASHI, S
影响因子：
48
作者：
Lorenz, H;Hailey, DW;Lippincott-Schwartz, J
通讯作者：
Lippincott-Schwartz, J
影响因子：
4.8
作者：
Mercer, Jason C.;DeHaven, Wayne I.;Putney, James W., Jr.
通讯作者：
Putney, James W., Jr.
DOI：
10.1073/pnas.0608358103
发表时间：
2006-11-07
影响因子：
11.1
作者：
Baba, Yoshihiro;Hayashit, Kenji;Kurosaki, Tomohiro
通讯作者：
Kurosaki, Tomohiro