Omnitemporal choreographies of all five STIM/Orai and IP(3)Rs underlie the complexity of mammalian Ca(2+) signaling.
Omnitemporal choreographies of all five STIM/Orai and IP(3)Rs underlie the complexity of mammalian Ca(2+) signaling.
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DOI：
10.1016/j.celrep.2021.108760
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发表时间：
2021-03-02
期刊：
影响因子：
8.8
通讯作者：
Trebak M
中科院分区：
文献类型：
--
作者：
Emrich SM;Yoast RE;Xin P;Arige V;Wagner LE;Hempel N;Gill DL;Sneyd J;Yule DI;Trebak M
基质相互作用分子（STIM 1/2）感知内质网（ER）Ca 2+耗竭并激活奥赖通道。然而，在生理激动剂刺激下天然STIM/奥赖蛋白之间的相互作用的编排是未知的。我们发现，五个STIM 1/2和Orai 1/2/3蛋白是非冗余的，并共同发挥作用，以确保哺乳动物Ca 2+信号的分级多样性。生理Ca 2+信号传导需要STIM 1/2、Orai 1/2/3和IP 3R之间的功能相互作用，确保受体介导的Ca 2+释放适合于Ca 2+进入和活化T细胞核因子（NFAT）活化。未激活的STIM 1/2的N端Ca 2+结合ER管腔结构域抑制IP 3R诱导的Ca 2+释放。激动剂强度和STIM 1/2激活的逐渐增加减轻IP 3R抑制。同时，激活的STIM 1/2 C末端差异与Orai 1/2/3的激动剂强度增加的相互作用。因此，所有五种STIM/奥赖和IP 3 R的协调和全时功能将激动剂刺激的强度转化为精确水平的Ca 2+信号传导和NFAT诱导，确保复杂哺乳动物Ca 2+信号传导的保真度。Ca 2+信号对细胞功能至关重要。Emrich等人表明，五种存储操作的STIM/奥赖蛋白是非冗余的。生理存储操作的通道活动是所有五个STIM 1/2和Orai 1/2/3蛋白及其与IP 3R的功能相互作用的全时编排，确保了Ca 2+信号传导和NFAT激活的保真度和多样性。
Stromal-interaction molecules (STIM1/2) sense endoplasmic reticulum (ER) Ca2+ depletion and activate Orai channels. However, the choreography of interactions between native STIM/Orai proteins under physiological agonist stimulation is unknown. We show that the five STIM1/2 and Orai1/2/3 proteins are non-redundant and function together to ensure the graded diversity of mammalian Ca2+ signaling. Physiological Ca2+ signaling requires functional interactions between STIM1/2, Orai1/2/3, and IP3Rs, ensuring that receptor-mediated Ca2+ release is tailored to Ca2+ entry and nuclear factor of activated T cells (NFAT) activation. The N-terminal Ca2+-binding ER-luminal domains of unactivated STIM1/2 inhibit IP3R-evoked Ca2+ release. A gradual increase in agonist intensity and STIM1/2 activation relieves IP3R inhibition. Concomitantly, activated STIM1/2 C termini differentially interact with Orai1/2/3 as agonist intensity increases. Thus, coordinated and omnitemporal functions of all five STIM/Orai and IP3Rs translate the strength of agonist stimulation to precise levels of Ca2+ signaling and NFAT induction, ensuring the fidelity of complex mammalian Ca2+ signaling. Ca2+ signals are crucial for cell function. Emrich et al. show that the five store-operated STIM/Orai proteins are non-redundant. Physiological store-operated channel activities are omnitemporal choreographies of all five STIM1/2 and Orai1/2/3 proteins and their functional interactions with IP3Rs, ensuring the fidelity and diversity of Ca2+ signaling and NFAT activation.
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影响因子：
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作者：
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通讯作者：
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影响因子：
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作者：
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DOI：
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发表时间：
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影响因子：
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