• 主题
高级搜索  >
历史搜索 清空历史
首页> 美国卫生研究院文献>The Journal of Biological Chemistry >Mechanism of Actin Filament Bundling by Fascin
【2h】

Mechanism of Actin Filament Bundling by Fascin

机译：Fascin的肌动蛋白丝捆扎机理。

代理获取
本网站仅为用户提供外文OA文献查询和代理获取服务，本网站没有原文。下单后我们将采用程序或人工为您竭诚获取高质量的原文，但由于OA文献来源多样且变更频繁，仍可能出现获取不到、文献不完整或与标题不符等情况，如果获取不到我们将提供退款服务。请知悉。
页面导航
  • 摘要
  • 著录项
  • 相似文献
  • 相关主题

摘要

Fascin is the main actin filament bundling protein in filopodia. Because of the important role filopodia play in cell migration, fascin is emerging as a major target for cancer drug discovery. However, an understanding of the mechanism of bundle formation by fascin is critically lacking. Fascin consists of four β-trefoil domains. Here, we show that fascin contains two major actin-binding sites, coinciding with regions of high sequence conservation in β-trefoil domains 1 and 3. The site in β-trefoil-1 is located near the binding site of the fascin inhibitor macroketone and comprises residue Ser-39, whose phosphorylation by protein kinase C down-regulates actin bundling and formation of filopodia. The site in β-trefoil-3 is related by pseudo-2-fold symmetry to that in β-trefoil-1. The two sites are ∼5 nm apart, resulting in a distance between actin filaments in the bundle of ∼8.1 nm. Residue mutations in both sites disrupt bundle formation in vitro as assessed by co-sedimentation with actin and electron microscopy and severely impair formation of filopodia in cells as determined by rescue experiments in fascin-depleted cells. Mutations of other areas of the fascin surface also affect actin bundling and formation of filopodia albeit to a lesser extent, suggesting that, in addition to the two major actin-binding sites, fascin makes secondary contacts with other filaments in the bundle. In a high resolution crystal structure of fascin, molecules of glycerol and polyethylene glycol are bound in pockets located within the two major actin-binding sites. These molecules could guide the rational design of new anticancer fascin inhibitors.
机译：Fascin是丝状伪足中主要的肌动蛋白丝捆绑蛋白。由于丝状伪足在细胞迁移中起着重要作用，因此fascin逐渐成为癌症药物发现的主要靶标。但是，对肌成束蛋白成束的机理的认识非常缺乏。 Fascin由四个β-三叶结构域组成。在这里，我们显示出fascin包含两个主要的肌动蛋白结合位点，与β-三叶结构域1和3中的高序列保守性区域相吻合。β-trefoil-1中的位点位于fascin抑制剂大酮和Faccin结合位点附近。包含残基Ser-39，其通过蛋白激酶C的磷酸化下调肌动蛋白束缚和丝状伪足的形成。 β-三叶-3中的位点与β-三叶-1中的位点具有伪2倍对称性。两个位点相距约5 nm，因此束中肌动蛋白丝之间的距离约为8.1 nm。通过肌动蛋白和电子显微镜的共同沉淀法评估，两个位点的残基突变都在体外破坏了束的形成，并严重破坏了成束纤维蛋白的细胞，通过挽救实验确定了丝状伪足的形成严重受损。 Fascin表面其他区域的突变也影响肌动蛋白的束缚和丝状伪足的形成，尽管程度较小，这表明，除了两个主要的肌动蛋白结合位点之外，fascin还与束中的其他细丝进行了二次接触。在fascin的高分辨率晶体结构中，甘油和聚乙二醇分子结合在位于两个主要肌动蛋白结合位点内的口袋中。这些分子可以指导新的抗癌fascin抑制剂的合理设计。

著录项

相似文献

  • 外文文献
  • 中文文献
  • 专利
代理获取

客服邮箱：kefu@zhangqiaokeyan.com

京公网安备：11010802029741号 ICP备案号：京ICP备15016152号-6 六维联合信息科技 (北京) 有限公司©版权所有

  • 客服微信

  • 服务号