Department of Biology, Rosenstiel Basic Medical Science Research Center, Brandeis University, Waltham, MA.
Bioengineering Department, Faculty of Biology, Lomonosov Moscow State University, Moscow, Russia.
J Cell Biol. 2018 Oct 1;217(10):3512-3530. doi: 10.1083/jcb.201803164. Epub 2018 Aug 3.
Formins are essential actin assembly factors whose activities are controlled by a diverse array of binding partners. Until now, most formin ligands have been studied on an individual basis, leaving open the question of how multiple inputs are integrated to regulate formins in vivo. Here, we show that the F-BAR domain of Hof1 interacts with the FH2 domain of the formin Bnr1 and blocks actin nucleation. Electron microscopy of the Hof1-Bnr1 complex reveals a novel dumbbell-shaped structure, with the tips of the F-BAR holding two FH2 dimers apart. Deletion of Hof1's F-BAR domain in vivo results in disorganized actin cables and secretory defects. The formin-binding protein Bud6 strongly alleviates Hof1 inhibition in vitro, and suppresses defects in vivo. Whereas Hof1 stably resides at the bud neck, we show that Bud6 is delivered to the neck on secretory vesicles. We propose that Hof1 and Bud6 functions are intertwined as a stationary inhibitor and a mobile activator, respectively.
formin 是肌动蛋白聚合所必需的组装因子，其活性受到多种结合配偶体的控制。到目前为止，大多数formin 配体都是单独研究的，这就留下了一个问题，即多个输入是如何整合起来在体内调节 formin 的。在这里，我们显示 Hof1 的 F-BAR 结构域与formin Bnr1 的 FH2 结构域相互作用并阻断肌动蛋白成核。Hof1-Bnr1 复合物的电子显微镜显示出一种新颖的哑铃状结构，F-BAR 的尖端将两个 FH2 二聚体分开。体内 Hof1 的 F-BAR 结构域缺失会导致肌动蛋白缆线紊乱和分泌缺陷。formin 结合蛋白 Bud6 在体外强烈缓解 Hof1 的抑制作用，并在体内抑制缺陷。虽然 Hof1 稳定地位于芽颈处，但我们表明 Bud6 是在分泌小泡上递送到颈部的。我们提出 Hof1 和 Bud6 的功能分别作为固定抑制剂和可移动激活剂交织在一起。
