Phospholipids regulate localization and activity of mDia1 formin
Phospholipids regulate localization and activity of mDia1 formin
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DOI：
10.1016/j.ejcb.2010.06.001
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发表时间：
2010-10-01
影响因子：
6.6
通讯作者：
Schleicher, Michael
中科院分区：
文献类型：
--
作者：
Ramalingam, Nagendran;Zhao, Hongxia;Schleicher, Michael
透明相关的形成蛋白（DRF）是一种大的多结构域蛋白质，其成核和组装线性肌动蛋白丝。活性Rho家族蛋白与GTP酶结合结构域（GBD）的结合触发了膜上的定位和大多数formin（如果不是全部的话）的活化。近年来，已广泛研究了GTdR对formins的调节，但对决定亚细胞分布或调节GTdR活性的其他分子机制仍知之甚少。在这里，我们提供的证据表明，活动和本地化的小鼠hmDia 1可以通过与磷脂的相互作用进行调节。mDia 1的磷脂结合位点是N-末端碱性结构域（BD）和C-末端区域的带正电荷残基簇。在与脂质双层结合后，mDia 1的N-末端区域诱导磷脂酰肌醇-4，5-二磷酸（PIP 2）的强烈聚集，并随后插入膜双层，从而将mDia 1锚定到重构的质膜。此外，磷脂与mDia 1的C-末端区域的相互作用导致其肌动蛋白丝组装活性的急剧降低。我们的数据表明，N-末端磷脂结合位点有助于锚formin在质膜，和磷脂的相互作用在C-末端功能作为一个开关瞬时失活。(C)2010年Elsevier GmbH。All rights reserved.
Diaphanous-related formins (DRFs) are large multi-domain proteins that nucleate and assemble linear actin filaments. Binding of active Rho family proteins to the GTPase-binding domain (GBD) triggers localization at the membrane and the activation of most formins if not all. In recent years GTPase regulation of formins has been extensively studied, but other molecular mechanisms that determine subcellular distribution or regulate formin activity have remained poorly understood. Here, we provide evidence that the activity and localization of mouse formin mDia1 can be regulated through interactions with phospholipids. The phospholipid-binding sites of mDia1 are clusters of positively charged residues in the N-terminal basic domain (BD) and at the C-terminal region. Upon binding to the lipid bilayer the N-terminal region of mDia1 induces strong clustering of phosphatidylinositol-4,5-bisphosphate (PIP2) and subsequently inserts into the membrane bilayer thus anchoring mDia1 to the reconstituted plasma membrane. In addition, an interaction of phospholipids with the C-terminal region of mDia1 causes a drastic reduction of its actin filament assembly activity. Our data suggest that the N-terminal phospholipid-binding sites help to anchor formins at the plasma membrane, and the interaction with phospholipids in the C-terminus functions as a switch for transient inactivation. (C) 2010 Elsevier GmbH. All rights reserved.