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首页> 外文期刊>Molecular and Cellular Biology >Myocardin-Related Transcription Factor A Activation by Competition with WH2 Domain Proteins for Actin Binding
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Myocardin-Related Transcription Factor A Activation by Competition with WH2 Domain Proteins for Actin Binding

机译：通过与WH2域蛋白竞争肌动蛋白结合而激活心肌相关转录因子A

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The myocardin-related transcription factors (MRTFs) are coactivators of serum response factor (SRF)-mediated gene expression. Activation of MRTF-A occurs in response to alterations in actin dynamics and critically requires the dissociation of repressive G-actin–MRTF-A complexes. However, the mechanism leading to the release of MRTF-A remains unclear. Here we show that WH2 domains compete directly with MRTF-A for actin binding. Actin nucleation-promoting factors, such as N-WASP and WAVE2, as well as isolated WH2 domains, including those of Spire2 and Cobl, activate MRTF-A independently of changes in actin dynamics. Simultaneous inhibition of Arp2-Arp3 or mutation of the CA region only partially reduces MRTF-A activation by N-WASP and WAVE2. Recombinant WH2 domains and the RPEL domain of MRTF-A bind mutually exclusively to cellular and purified G-actin in vitro. The competition by different WH2 domains correlates with MRTF-SRF activation. Following serum stimulation, nonpolymerizable actin dissociates from MRTF-A, and de novo formation of the G-actin–RPEL complex is impaired by a transferable factor. Our work demonstrates that WH2 domains activate MRTF-A and contribute to target gene regulation by a competitive mechanism, independently of their role in actin filament formation.
机译：心肌相关转录因子（MRTF）是血清反应因子（SRF）介导的基因表达的共激活因子。 MRTF-A的激活是由于肌动蛋白动力学的变化而发生的，并且非常需要抑制性G-肌动蛋白-MRTF-A复合体的解离。但是，导致MRTF-A释放的机制仍不清楚。在这里，我们显示WH2域直接与MRTF-A竞争肌动蛋白结合。肌动蛋白成核促进因子（例如N-WASP和WAVE2）以及分离的WH2​​域（包括Spire2和Cobl的WH2域）独立于肌动蛋白动力学变化激活MRTF-A。同时抑制Arp2-Arp3或CA区域的突变仅部分降低了N-WASP和WAVE2对MRTF-A的激活。 MRTF-A的重组WH2结构域和RPEL结构域在体外分别与细胞和纯化的G-肌动蛋白结合。不同WH2域的竞争与MRTF-SRF激活相关。血清刺激后，不可聚合的肌动蛋白会从MRTF-A上解离，G-肌动蛋白-RPEL复合物的从头开始形成会受到可转移因子的损害。我们的工作表明WH2域激活MRTF-A并通过竞争机制促进靶基因调节，而与它们在肌动蛋白丝形成中的作用无关。

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