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Tracing the evolutionary history of Ca2+-signaling modulation by human Bcl-2: Insights from the Capsaspora owczarzaki IP3 receptor ortholog
Biochimica et Biophysica Acta (BBA) - Molecular Cell Research ( IF 4.6 ) Pub Date : 2021-08-14 , DOI: 10.1016/j.bbamcr.2021.119121
Nicolas Rosa 1 , Victoria Shabardina 2 , Hristina Ivanova 1 , Arnau Sebé-Pedrós 3 , David I Yule 4 , Geert Bultynck 1
Affiliation  

Recently, a functional IP3R ortholog (CO.IP3R-A) capable of IP3-induced Ca2+ release has been discovered in Capsaspora owczarzaki, a close unicellular relative to Metazoa. In contrast to mammalian IP3Rs, CO.IP3R-A is not modulated by Ca2+, ATP or PKA. Protein-sequence analysis revealed that CO.IP3R-A contained a putative binding site for anti-apoptotic Bcl-2, although Bcl-2 was not detected in Capsaspora owczarzaki and only appeared in Metazoa. Here, we examined whether human Bcl-2 could form a complex with CO.IP3R-A channels and modulate their Ca2+-flux properties using ectopic expression approaches in a HEK293 cell model in which all three IP3R isoforms were knocked out. We demonstrate that human Bcl-2 via its BH4 domain could functionally interact with CO.IP3R-A, thereby suppressing Ca2+ flux through CO.IP3R-A channels. The BH4 domain of Bcl-2 was sufficient for interaction with CO.IP3R-A channels. Moreover, mutating the Lys17 of Bcl-2's BH4 domain, the residue critical for Bcl-2-dependent modulation of mammalian IP3Rs, abrogated Bcl-2's ability to bind and inhibit CO.IP3R-A channels. Hence, this raises the possibility that a unicellular ancestor of animals already had an IP3R that harbored a Bcl-2-binding site. Bcl-2 proteins may have evolved as controllers of IP3R function by exploiting this pre-existing site, thereby counteracting Ca2+-dependent apoptosis.



中文翻译:

追踪人类 Bcl-2 对 Ca2+ 信号调节的进化历史:来自 Capsaspora owczarzaki IP3 受体直系同源物的见解

最近,在Capsaspora owczarzaki 中发现了一种能够 IP 3诱导 Ca 2+释放的功能性 IP 3 R 直向同源物(CO.IP 3 R-A),这是一种与后生动物相关的紧密单细胞。与哺乳动物 IP 3 Rs 相比,CO.IP 3 R-A 不受 Ca 2+、ATP 或 PKA 的调节。蛋白质序列分析表明,CO.IP 3 R-A 含有一个推定的抗凋亡 Bcl-2 结合位点,尽管 Bcl-2 在Capsaspora owczarzaki 中未检测到,仅出现在后生动物中。在这里,我们检查了人类 Bcl-2 是否可以与 CO.IP 3 R-A 通道形成复合物并调节它们的 Ca在 HEK293 细胞模型中使用异位表达方法的2+ -flux 特性,其中所有三个 IP 3 R 同种型都被敲除。我们证明人类 Bcl-2 通过其 BH4 域可以在功能上与 CO.IP 3 R-A相互作用,从而抑制通过 CO.IP 3 R-A 通道的Ca 2+通量。Bcl-2 的 BH4 域足以与 CO.IP 3 R-A 通道相互作用。此外,突变 Bcl-2 的 BH4 结构域的 Lys17,这是 Bcl-2 依赖性调节哺乳动物 IP 3 Rs 的关键残基,废除了 Bcl-2 结合和抑制 CO.IP 3 R-A 通道的能力。因此,这增加了动物的单细胞祖先已经拥有 IP 的可能性3 R 含有 Bcl-2 结合位点。Bcl-2 蛋白可能已经通过利用这个预先存在的位点进化为 IP 3 R 功能的控制器,从而抵消 Ca 2+依赖性细胞凋亡。

更新日期:2021-08-20
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