Intrinsic Disorder Mediates Cooperative Signal Transduction in STIM1
Intrinsic Disorder Mediates Cooperative Signal Transduction in STIM1
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DOI：
10.1016/j.jmb.2014.03.006
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发表时间：
2014-05-15
影响因子：
5.6
通讯作者：
Standley, Daron M.
中科院分区：
文献类型：
--
作者：
Furukawa, Yukio;Teraguchi, Shunsuke;Standley, Daron M.
蛋白质内无序结构域在蛋白质相互作用中引入协同效应，在信号转导网络中发挥重要作用。与结合后变得有序的固有无序结构域不同，基质相互作用分子（STIM）1中的EF-SAM结构域的不同之处在于，它在单体状态下是有序的，在其低聚状态下是部分未折叠的，两种状态的群体取决于局部Ca 2+浓度。寡聚化的STIM 1，触发细胞外Ca 2+内流，表现出与当地内质网Ca 2+浓度的协同性。虽然低聚反应的生理重要性是公认的，所观察到的协同性的机制是未知的。在这里，我们研究了响应的STIM 1 EF-SAM域的变化，在Ca 2+浓度的基础上，在体外实验中使用数学建模。我们发现，EF-SAM结构域部分展开和二聚化合作相对于Ca 2+浓度，希尔系数和半最大激活浓度非常接近的值在体内观察到的STIM 1再分配和细胞外Ca 2+流入。我们的数学模型的二聚反应同意定量与我们的分析ultracenthegation为基础的测量和先前发表的自由能展开。这些结果的一个简单解释是，Ca 2+损失有效地作为变性剂，使合作的二聚化和强大的信号转导。我们提出了一个结构模型的Ca 2 +-未结合的EF-SAM域，这是一致的广泛的证据，包括抗蛋白水解裂解的推定的二聚化部分。(C)2014作者由爱思唯尔有限公司出版。这是一个开放获取的文章下CC BY-NC-ND许可证
Intrinsically disordered domains have been reported to play important roles in signal transduction networks by introducing cooperativity into protein-protein interactions. Unlike intrinsically disordered domains that become ordered upon binding, the EF-SAM domain in the stromal interaction molecule (STIM) 1 is distinct in that it is ordered in the monomeric state and partially unfolded in its oligomeric state, with the population of the two states depending on the local Ca2+ concentration. The oligonnerization of STIM1, which triggers extracellular Ca2+ influx, exhibits cooperativity with respect to the local endoplasmic reticulum Ca2+ concentration. Although the physiological importance of the oligomerization reaction is well established, the mechanism of the observed cooperativity is not known. Here, we examine the response of the STIM1 EF-SAM domain to changes in Ca2+ concentration using mathematical modeling based on in vitro experiments. We find that the EF-SAM domain partially unfolds and dimerizes cooperatively with respect to Ca2+ concentration, with Hill coefficients and half-maximal activation concentrations very close to the values observed in vivo for STIM1 redistribution and extracellular Ca2+ influx. Our mathematical model of the dimerization reaction agrees quantitatively with our analytical ultracentrifugation-based measurements and previously published free energies of unfolding. A simple interpretation of these results is that Ca2+ loss effectively acts as a denaturant, enabling cooperative dimerization and robust signal transduction. We present a structural model of the Ca2+-unbound EF-SAM domain that is consistent with a wide range of evidence, including resistance to proteolytic cleavage of the putative dimerization portion. (C) 2014 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license