PDF(Pubmed)
Abstract：
We previously identified talin rod domain-containing protein 1 (TLNRD1) as a potent actin-bundling protein in vitro. Here, we report that TLNRD1 is expressed in the vasculature in vivo. Its depletion leads to vascular abnormalities in vivo and modulation of endothelial cell monolayer integrity in vitro. We demonstrate that TLNRD1 is a component of the cerebral cavernous malformations (CCM) complex through its direct interaction with CCM2, which is mediated by a hydrophobic C-terminal helix in CCM2 that attaches to a hydrophobic groove on the four-helix domain of TLNRD1. Disruption of this binding interface leads to CCM2 and TLNRD1 accumulation in the nucleus and actin fibers. Our findings indicate that CCM2 controls TLNRD1 localization to the cytoplasm and inhibits its actin-bundling activity and that the CCM2-TLNRD1 interaction impacts endothelial actin stress fiber and focal adhesion formation. Based on these results, we propose a new pathway by which the CCM complex modulates the actin cytoskeleton and vascular integrity.
摘要：
我们先前在体外鉴定了含滑石杆结构域的蛋白1（TLNRD1）为有效的肌动蛋白捆绑蛋白。这里,我们报道TLNRD1在体内血管中表达。它的消耗导致体内血管异常和体外内皮细胞单层完整性的调节。我们证明TLNRD1是脑海绵状畸形（CCM）复合物的组成部分，通过其与CCM2的直接相互作用，这是由CCM2中的疏水C末端螺旋介导的，该螺旋附着于TLNRD1的四螺旋结构域上的疏水沟。该结合界面的破坏导致CCM2和TLNRD1在细胞核和肌动蛋白纤维中的积累。我们的发现表明CCM2控制TLNRD1在细胞质中的定位并抑制其肌动蛋白捆绑活性，并且CCM2-TLNRD1相互作用影响内皮肌动蛋白应力纤维和粘着斑的形成。基于这些结果,我们提出了CCM复合物调节肌动蛋白细胞骨架和血管完整性的新途径。
