IRBIT suppresses IP3 receptor activity by competing with IP3 for the common binding site on the IP3 receptor
IRBIT suppresses IP3 receptor activity by competing with IP3 for the common binding site on the IP3 receptor
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DOI：
10.1016/j.molcel.2006.05.017
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发表时间：
2006-06-23
期刊：
影响因子：
16
通讯作者：
Mikoshiba, Katsuhiko
中科院分区：
文献类型：
--
作者：
Ando, Hideaki;Mizutani, Akihiro;Mikoshiba, Katsuhiko
1，4，5-三磷酸肌醇（IP 3）受体（IP（3）Rs）是IP 3门控的细胞内Ca 2+通道。我们以前确定了一个IP 3 R结合蛋白，伊尔比特，它结合到IP 3 R的IP 3结合结构域，并在IP 3的存在下从IP 3 R解离。在本研究中，我们表明，伊尔比特通过[H-3] IP 3结合试验，体外Ca 2+释放试验，和完整细胞的Ca 2+成像与IP 3竞争抑制IP 3 R的激活。伊尔比特的多丝氨酸磷酸化是结合所必需的，IP 3 R中识别IP 3的12个关键氨基酸中的10个参与了与伊尔比特的结合。我们提出了一种独特的模式，其中IP 3的敏感性调节伊尔比特作为一个内源性的“假配体”，其抑制活性可以通过其磷酸化状态进行调制。
The inositol 1,4,5-trisphosphate (IP3) receptors (IP(3)Rs) are IP3-gated intracellular Ca2+ channels. We previously identified an IP3R binding protein, IRBIT, which binds to the IP3 binding domain of IP3R and is dissociated from IP3R in the presence of IP3- In the present study, we showed that IRBIT suppresses the activation of IP3R by competing with IP3 by [H-3]IP3 binding assays, in vitro Ca2+ release assays, and Ca2+ imaging of intact cells. Multiserine phosphorylation of IRBIT was essential for the binding, and 10 of the 12 key amino acids in IP3R for IP3 recognition participated in binding to IRBIT. We propose a unique mode of IP3R regulation in which IP3 sensitivity is regulated by IRBIT acting as an endogenous "pseudoligand" whose inhibitory activity can be modulated by its phosphorylation status.