Selective regulation of IP3-receptor-mediated Ca2+ signaling and apoptosis by the BH4 domain of Bcl-2 versus Bcl-Xl.
Selective regulation of IP3-receptor-mediated Ca2+ signaling and apoptosis by the BH4 domain of Bcl-2 versus Bcl-Xl.
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DOI：
10.1038/cdd.2011.97
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发表时间：
2012-02
影响因子：
12.4
通讯作者：
中科院分区：
文献类型：
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作者：
抗凋亡B细胞淋巴瘤2（Bcl-2）通过其BH 4结构域靶向肌醇1，4，5-三磷酸受体（IP 3R），从而抑制IP 3R Ca 2+通量特性并保护免于Ca 2+依赖性凋亡。在此，我们直接比较了BH 4-Bcl-2和BH 4-Bcl-Xl对IP 3R的抑制。与BH 4-Bcl-2相反，BH 4-Bcl-Xl既不结合IP 3R的调节结构域，也不抑制透化和完整细胞中IP 3诱导的Ca 2+释放（IICR）。我们鉴定了BH 4-Bcl-2（Lys 17）中的关键残基，其在BH 4-Bcl-Xl（Asp 11）中不保守。在BH 4-Bcl-2中将Lys 17改变为Asp完全消除了其IP 3R结合和抑制特性，而在BH 4-Bcl-Xl中将Asp 11改变为Lys诱导了IP 3R结合和抑制。BH 4-Bcl-2和BH 4-Bcl-Xl之间IP 3R调节的这种差异控制它们的抗凋亡作用。虽然BH 4-Bcl-2和BH 4-Bcl-Xl都具有抗凋亡活性，但BH 4-Bcl-2比BH 4-Bcl-Xl更有效。BH 4-Bcl-2的作用依赖于其与IP 3Rs的结合，而BH 4-Bcl-Xl的作用不依赖于其与IP 3Rs的结合。与IP 3R结合特性一致，BH 4-Bcl-2和BH 4-Bcl-Xl的抗凋亡活性通过Lys/Asp取代来调节。将全长Bcl-2中的Lys 17改变为Asp显著降低了其与IP 3R的结合、其抑制IICR的能力以及其对凋亡刺激的保护。因此，BH 4-Bcl-2和BH 4-Bcl-Xl之间的单个氨基酸差异是这些功能结构域对IP 3Rs和Ca 2+驱动的细胞凋亡的差异调节的基础。该残基的突变影响Bcl-2在Ca 2+信号传导和凋亡中的功能。
Antiapoptotic B-cell lymphoma 2 (Bcl-2) targets the inositol 1,4,5-trisphosphate receptor (IP3R) via its BH4 domain, thereby suppressing IP3R Ca2+-flux properties and protecting against Ca2+-dependent apoptosis. Here, we directly compared IP3R inhibition by BH4-Bcl-2 and BH4-Bcl-Xl. In contrast to BH4-Bcl-2, BH4-Bcl-Xl neither bound the modulatory domain of IP3R nor inhibited IP3-induced Ca2+ release (IICR) in permeabilized and intact cells. We identified a critical residue in BH4-Bcl-2 (Lys17) not conserved in BH4-Bcl-Xl (Asp11). Changing Lys17 into Asp in BH4-Bcl-2 completely abolished its IP3R-binding and -inhibitory properties, whereas changing Asp11 into Lys in BH4-Bcl-Xl induced IP3R binding and inhibition. This difference in IP3R regulation between BH4-Bcl-2 and BH4-Bcl-Xl controls their antiapoptotic action. Although both BH4-Bcl-2 and BH4-Bcl-Xl had antiapoptotic activity, BH4-Bcl-2 was more potent than BH4-Bcl-Xl. The effect of BH4-Bcl-2, but not of BH4-Bcl-Xl, depended on its binding to IP3Rs. In agreement with the IP3R-binding properties, the antiapoptotic activity of BH4-Bcl-2 and BH4-Bcl-Xl was modulated by the Lys/Asp substitutions. Changing Lys17 into Asp in full-length Bcl-2 significantly decreased its binding to the IP3R, its ability to inhibit IICR and its protection against apoptotic stimuli. A single amino-acid difference between BH4-Bcl-2 and BH4-Bcl-Xl therefore underlies differential regulation of IP3Rs and Ca2+-driven apoptosis by these functional domains. Mutating this residue affects the function of Bcl-2 in Ca2+ signaling and apoptosis.
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影响因子：
32.4
作者：
Jones, Russell G.;Bui, Thi;Thompson, Craig B.
通讯作者：
Thompson, Craig B.
DOI：
10.1073/pnas.152571899
发表时间：
2002-07-23
影响因子：
11.1
作者：
Li, C;Fox, CJ;Thompson, CB
通讯作者：
Thompson, CB
DOI：
10.1073/pnas.0409650102
发表时间：
2005-02-01
影响因子：
11.1
作者：
Boehning, D;van Rossum, DB;Snyder, SH
通讯作者：
Snyder, SH
影响因子：
4.8
作者：
Eckenrode, Emily F.;Yang, Jun;White, Carl
通讯作者：
White, Carl
影响因子：
12.4
作者：
Decrock, E.;De Vuyst, E.;Leybaert, L.
通讯作者：
Leybaert, L.