Gated regulation of CRAC channel ion selectivity by STIM1.
Gated regulation of CRAC channel ion selectivity by STIM1.
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DOI：
10.1038/nature10752
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发表时间：
2012-01-25
期刊：
影响因子：
64.8
通讯作者：
Prakriya, Murali
中科院分区：
文献类型：
--
作者：
McNally, Beth A.;Somasundaram, Agila;Yamashita, Megumi;Prakriya, Murali
离子通道的两个定义功能特征是离子选择性和通道门控。离子选择性通常被认为是开放通道结构的不可变属性，而门控涉及开放和关闭通道状态之间的转变，通常不会改变离子选择性。在钙离子释放激活钙通道(CRAC)中，CRAC通道激活剂STIM1(间质相互作用分子1)对通道门控的分子机制尚不清楚。CRAC通道具有非常高的钙离子选择性，在许多真核细胞中产生持续的[钙]i升高是基因表达和效应器功能所必需的。在这里，我们探索了CRAC通道蛋白Orai1中STIM1门控机制的中心特征，并确定V102，一种位于孔外区域的残基，是通道门的候选。V102的突变产生了构成活性的CRAC通道，即使在没有STIM1的情况下也是开放的。出乎意料的是，尽管没有STIM1的V102突变通道对钙离子没有选择性，但它们的钙选择性被与STIM1的相互作用剂量依赖性地提高。在野生型(WT)Orai1通道中，通过增加直接连接到Orai1通道的STIM1激活结构域的数量，也可以同样地增强钙离子的选择性。因此，精致的钙选择性不是CRAC通道的固有属性，而是STIM1赋予非选择性Orai1通道的可调特征。我们的结果表明，STIM1介导的CRAC通道的门控是通过一种不寻常的机制发生的，其中渗透和门控是紧密耦合的。
Two defining functional features of ion channels are ion selectivity and channel gating. Ion selectivity is generally considered an immutable property of the open channel structure, whereas gating involves transitions between open and closed channel states typically without changes in ion selectivity . In store-operated Ca2+ release-activated Ca2+ (CRAC) channels, the molecular mechanism of channel gating by the CRAC channel activator, STIM1 (stromal interaction molecule 1) remains unknown. CRAC channels are distinguished by an extraordinarily high Ca2+ selectivity and are instrumental in generating sustained [Ca2+]i elevations necessary for gene expression and effector function in many eukaryotic cells . Here, we probed the central features of the STIM1 gating mechanism in the CRAC channel protein, Orai1, and identified V102, a residue located in the extracellular region of the pore, as a candidate for the channel gate. Mutations at V102 produced constitutively active CRAC channels that were open even in the absence of STIM1. Unexpectedly, although STIM1-free V102 mutant channels were not Ca2+-selective, their Ca2+ selectivity was dose-dependently boosted by interactions with STIM1. Similar enhancement of Ca2+ selectivity also occurred in wild-type (WT) Orai1 channels by increasing the number of STIM1 activation domains directly tethered to Orai1 channels. Thus, exquisite Ca2+ selectivity is not an intrinsic property of CRAC channels, but rather a tunable feature bestowed on otherwise non-selective Orai1 channels by STIM1. Our results demonstrate that STIM1-mediated gating of CRAC channels occurs through an unusual mechanism wherein permeation and gating are closely coupled.
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影响因子：
64.5
作者：
Feng M;Grice DM;Faddy HM;Nguyen N;Leitch S;Wang Y;Muend S;Kenny PA;Sukumar S;Roberts-Thomson SJ;Monteith GR;Rao R
通讯作者：
Rao R
DOI：
10.1073/pnas.1101664108
发表时间：
2011-08-09
影响因子：
11.1
作者：
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通讯作者：
Lewis, Richard S.
影响因子：
64.8
作者：
Prakriya, Murali;Feske, Stefan;Hogan, Patrick G.
通讯作者：
Hogan, Patrick G.
影响因子：
64.8
作者：
Yeromin, Andriy V.;Zhang, Shenyuan L.;Cahalan, Michael D.
通讯作者：
Cahalan, Michael D.
影响因子：
4.8
作者：
Schindl, Rainer;Bergsmann, Judith;Romanin, Christoph
通讯作者：
Romanin, Christoph