The Bcl-2 Protein Family Member Bok Binds to the Coupling Domain of Inositol 1,4,5-Trisphosphate Receptors and Protects Them from Proteolytic Cleavage
The Bcl-2 Protein Family Member Bok Binds to the Coupling Domain of Inositol 1,4,5-Trisphosphate Receptors and Protects Them from Proteolytic Cleavage
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DOI：
10.1074/jbc.m113.496570
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发表时间：
2013-08-30
影响因子：
4.8
通讯作者：
Wojcikiewicz, Richard J. H.
中科院分区：
文献类型：
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作者：
Schulman, Jacqualyn J.;Wright, Forrest A.;Wojcikiewicz, Richard J. H.
Bok是Bcl-2蛋白家族的成员，其控制内在凋亡。Bok与促凋亡蛋白巴克和Bax最密切相关，但与巴克和Bax相反，对其细胞作用知之甚少。在这里，我们报告说，博克强烈和组成性结合肌醇1，4，5-三磷酸受体（IP（3）Rs），蛋白质，形成四聚体钙通道的内质网（ER）膜和管理释放的ER钙储存。Bok与IP（3）R1和IP（3）R2的结合最强，与IP（3）R3的结合几乎不强，在表达大量IP（3）R的细胞中，基本上所有细胞Bok都与IP（3）R结合。与IP（3）Rs的结合似乎是由假定的Bok的BH 4结构域介导的，对接位点定位于IP（3）Rs偶联结构域（IP（3）R1的氨基酸1895 - 1903）内的一个小区域，该区域邻近许多调节位点，包括蛋白水解位点。关于Bok-IP 3R结合的可能作用，观察到以下：（i）Bok似乎不控制IP（3）Rs释放ER钙储存的能力，（ii）Bok调节IP 3R表达，（iii）肌醇1，4，5-三磷酸依赖性细胞信号传导的持续激活导致Bok通过泛素-蛋白酶体途径降解，其方式与IP 3R降解平行，和（iv）在细胞凋亡过程中，Bok保护IP（3）Rs免受胰凝乳蛋白酶（体外）或caspase-3（体内）的蛋白水解。总的来说，这些数据表明Bok与IP（3）Rs强烈且组成性地结合，并且这种结合的最重要的结果似乎是保护IP（3）Rs免受蛋白水解。因此，Bok可能在细胞凋亡过程中控制IP 3R的裂解和活性。
Bok is a member of the Bcl-2 protein family that controls intrinsic apoptosis. Bok is most closely related to the pro-apoptotic proteins Bak and Bax, but in contrast to Bak and Bax, very little is known about its cellular role. Here we report that Bok binds strongly and constitutively to inositol 1,4,5-trisphosphate receptors (IP(3)Rs), proteins that form tetrameric calcium channels in the endoplasmic reticulum (ER) membrane and govern the release of ER calcium stores. Bok binds most strongly to IP(3)R1 and IP(3)R2, and barely to IP(3)R3, and essentially all cellular Bok is IP3R bound in cells that express substantial amounts of IP(3)Rs. Binding to IP(3)Rs appears to be mediated by the putative BH4 domain of Bok and the docking site localizes to a small region within the coupling domain of IP(3)Rs (amino acids 18951903 of IP(3)R1) that is adjacent to numerous regulatory sites, including sites for proteolysis. With regard to the possible role of Bok-IP3R binding, the following was observed: (i) Bok does not appear to control the ability of IP(3)Rs to release ER calcium stores, (ii) Bok regulates IP3R expression, (iii) persistent activation of inositol 1,4,5-trisphosphate-dependent cell signaling causes Bok degradation by the ubiquitin-proteasome pathway, in a manner that parallels IP3R degradation, and (iv) Bok protects IP(3)Rs from proteolysis, either by chymotrypsin in vitro or by caspase-3 in vivo during apoptosis. Overall, these data show that Bok binds strongly and constitutively to IP(3)Rs and that the most significant consequence of this binding appears to be protection of IP(3)Rs from proteolysis. Thus, Bok may govern IP3R cleavage and activity during apoptosis.