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Bcl-2 and FKBP12 bind to IP3 and ryanodine receptors at overlapping sites: the complexity of protein-protein interactions for channel regulation

机译:Bcl-2和FKBP12在重叠的位点结合IP3和ryanodine受体:通道调节中蛋白相互作用的复杂性

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摘要

The 12-kDa and 12.6-kDa FK506-binding proteins, FKBP12 and FKBP12.6, have been implicated in the binding to and the regulation of ryanodine receptors (RyRs) and inositol 1,4,5-trisphosphate receptors (IP3Rs), both tetrameric intracellular Ca2+-release channels. While the amino acid sequences responsible for FKBP12 binding to RyRs are conserved in IP3Rs, FKBP12 binding to IP3Rs has been questioned and could not be observed in various experimental models. Nevertheless, conservation of these residues in the different IP3R isoforms and during evolution suggested that they could harbour an important regulatory site critical for IP3R-channel function. Recently, it has become clear that in IP3Rs, this site was targeted by B-cell lymphoma 2 (Bcl-2) via its BH4 domain, thereby dampening IP3R-mediated Ca2+ flux and preventing pro-apoptotic Ca2+ signalling. Furthermore, vice versa, the presence of the corresponding site in RyRs implied that Bcl-2 proteins could associate with and regulate RyR channels. Recently, the existence of endogenous RyR/Bcl-2 complexes has been identified in primary hippocampal neurons. Like for IP3Rs, binding of Bcl-2 to RyRs also involved its BH4 domain and suppressed RyR-mediated Ca2+ release. We therefore propose that the originally identified FKBP12-binding site in IP3Rs is a region critical for controlling IP3R-mediated Ca2+ flux by recruiting Bcl-2 rather than FKBP12. Although we hypothesize that anti-apoptotic Bcl-2 proteins, but not FKBP12, are the main physiological inhibitors of IP3Rs, we cannot exclude that Bcl-2 could help engaging FKBP12 (or other FKBP isoforms) to the IP3R, potentially via calcineurin.
机译:12 kDa和12.6 kDa FK506结合蛋白FKBP12和FKBP12.6参与了对赖诺丹碱受体(RyRs)和肌醇1,4,5-三磷酸受体(IP3Rs)的结合和调节四聚体细胞内Ca2 +释放通道。虽然负责FKBP12与RyRs结合的氨基酸序列在IP3R中是保守的,但对FKBP12与IP3Rs的结合却受到质疑,在各种实验模型中均未观察到。尽管如此,这些残基在不同的IP3R同工型中以及进化过程中的保守性表明,它们可能具有重要的调控位点,对IP3R通道功能至关重要。最近,已经清楚的是,在IP3R中,该位点通过其BH4结构域被B细胞淋巴瘤2(Bcl-2)靶向,从而抑制IP3R介导的Ca2 +通量并防止促凋亡Ca2 +信号传导。此外,反之亦然,RyRs中相应位点的存在暗示Bcl-2蛋白可以与RyR通道结合并调节其通道。最近,已在原代海马神经元中发现了内源性RyR / Bcl-2复合物的存在。像IP3R一样,Bcl-2与RyR的结合也涉及其BH4结构域并抑制RyR介导的Ca2 +释放。因此,我们建议IP3Rs中最初识别的FKBP12结合位点是通过募集Bcl-2而非FKBP12来控制IP3R介导的Ca2 +通量的关键区域。尽管我们假设抗凋亡的Bcl-2蛋白而不是FKBP12是IP3R的主要生理抑制剂,但我们不能排除Bcl-2可能通过钙调神经磷酸酶帮助FKBP12(或其他FKBP同工型)与IP3R结合。

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