The Regulation Mechanism for the Auto-Inhibition of Binding of Human Filamin A to Integrin
The Regulation Mechanism for the Auto-Inhibition of Binding of Human Filamin A to Integrin
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DOI：
10.1016/j.jmb.2009.08.035
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发表时间：
2009-10-30
影响因子：
5.6
通讯作者：
Ylanne, Jari
中科院分区：
文献类型：
--
作者：
Pentikainen, Ulla;Ylanne, Jari
粘附受体传递生化信号和机械力穿过细胞膜的能力取决于与肌动蛋白细胞骨架的相互作用。人微丝蛋白是连接整联蛋白与细胞骨架的大肌动蛋白交联蛋白。细丝蛋白与β整联蛋白的胞质尾区结合已显示可阻止细胞中整联蛋白的活化，这对于控制细胞粘附和迁移是重要的。然而，细丝蛋白与整联蛋白结合的分子水平机制尚不清楚，因为最近证实细丝蛋白经历整联蛋白结合的分子内自抑制。在这项研究中，使用操纵分子动力学模拟，我们发现，机械力施加到细丝蛋白可以暴露隐藏的整合素结合位点。这所需的力大大低于细丝蛋白免疫球蛋白结构域展开的力。机械力诱导的细丝蛋白的展开和整联蛋白结合位点的暴露通过稳定的中间体发生，其中整联蛋白结合是可能的。因此，我们的研究结果支持细丝蛋白的作用，作为一个mechanotransducer，因为力诱导的构象变化允许结合的整合素和其他跨膜和细胞内蛋白。这种观察到的力诱导的构象变化也可能是参与调节整合素活化的可能机制之一。(c)2009爱思唯尔有限公司保留所有权利。
The ability of adhesion receptors to transmit biochemical signals and mechanical force across cell membranes depends on interactions with the actin cytoskeleton. Human filamins are large actin cross-linking proteins that connect integrins to the cytoskeleton. Filamin binding to the cytoplasmic tail of beta integrins has been shown to prevent integrin activation m cells, which is important for controlling cell adhesion and migration. The molecular-level mechanism for filamin binding to integrin has been unclear, however, as it was recently demonstrated that filamin undergoes intramolecular auto-inhibition of integrin binding. In this study, using steered molecular dynamics simulations, we found that mechanical force applied to filamin can expose cryptic integrin binding sites. The forces required for this are considerably lower than those for filamin immunoglobulin domain unfolding. The mechanical-force-induced unfolding of filamin and exposure of integrin binding sites occur through stable intermediates where integrin binding is possible. Accordingly, our results support filamin's role as a mechanotransducer, since force-induced conformational changes allow binding of integrin and other transmembrane and intracellular proteins. This observed force-induced conformational change can also be one of possible mechanisms involved in the regulation of integrin activation. (c) 2009 Elsevier Ltd. All rights reserved.