Mechanotransduction in talin through the interaction of the R8 domain with DLC1.
Mechanotransduction in talin through the interaction of the R8 domain with DLC1.
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DOI：
10.1371/journal.pbio.2005599
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发表时间：
2018-07
期刊：
影响因子：
9.8
通讯作者：
Del Río Hernández A
中科院分区：
文献类型：
--
作者：
Haining AWM;Rahikainen R;Cortes E;Lachowski D;Rice A;von Essen M;Hytönen VP;Del Río Hernández A
蛋白质的机械展开是一种力转导的细胞机制，对细胞命运具有潜在的广泛影响。尽管如此，蛋白质解折叠引发差异下游信号通路的机制仍然知之甚少。在这里，我们使用蛋白质工程、原子力显微镜和生物物理工具来描述蛋白质展开如何控制细胞力学。肝癌删除 1 (DLC1) 是 Ras 同源家族成员 A (RhoA) 和细胞收缩性的负调节因子，当定位于与折叠距蛋白结合的粘着斑时，可调节细胞行为。使用对力诱导的 R8 结构域展开具有抗性的 talin 突变体，我们发现 talin 展开决定了 DLC1 下游信号传导，从而决定了细胞力学。我们认为这种新的力转导机制可能对多种相关的细胞过程产生影响。力诱导的构象变化和蛋白质结构域的展开是力转导的基石，并调节蛋白质与其他分子的相互作用。 Talin 是粘着斑中的一种重要分子，也是同时连接细胞膜中整合素受体与肌动蛋白细胞骨架的少数蛋白质之一。由于细胞骨架的收缩性质，这种桥接位置使talin沿其长度受到力的作用。在这项工作中，我们研究了 R8 结构域展开对肝癌缺失 1 (DLC1) 下游活性的影响，DLC1 结合 talin R8 结构域并负向调节 Ras 同源物家族成员 A (RhoA)。我们创建了具有抗机械展开的 R8 结构域的 talin 突变体，并观察到表达这些 talin 突变体的细胞改变了粘着斑动力学模式并降低了肌动球蛋白收缩水平。这导致牵引力降低和细胞迁移减少。我们提出了一种新颖的力控制分子开关，它改进了talin介导的粘着斑激活机制，在粘着斑成熟过程中提供负反馈。这种talin介导的机制的更广泛的影响需要阐明，因为它可能调节多种细胞事件。
The mechanical unfolding of proteins is a cellular mechanism for force transduction with potentially broad implications in cell fate. Despite this, the mechanism by which protein unfolding elicits differential downstream signalling pathways remains poorly understood. Here, we used protein engineering, atomic force microscopy, and biophysical tools to delineate how protein unfolding controls cell mechanics. Deleted in liver cancer 1 (DLC1) is a negative regulator of Ras homolog family member A (RhoA) and cell contractility that regulates cell behaviour when localised to focal adhesions bound to folded talin. Using a talin mutant resistant to force-induced unfolding of R8 domain, we show that talin unfolding determines DLC1 downstream signalling and, consequently, cell mechanics. We propose that this new mechanism of mechanotransduction may have implications for a wide variety of associated cellular processes. Mechano-induced conformational changes and the unfolding of protein domains are cornerstones of mechanotransduction and regulate the interaction of proteins with other molecules. Talin is a prominent molecule in focal adhesions and one of the few proteins that simultaneously connects integrin receptors in the cell membrane with the actin cytoskeleton. This bridging position, owing to the cytoskeleton’s contractile nature, exposes talin to forces along its length. In this work, we studied the implications of the R8 domain unfolding in the downstream activity of deleted in liver cancer 1 (DLC1), which binds the talin R8 domain and negatively regulates Ras homolog family member A (RhoA). We created a talin mutant with the R8 domain resistant to mechanical unfolding and observed that cells expressing these talin mutants have altered patterns of focal adhesion dynamics and lower levels of actomyosin contraction. This leads to decreased traction forces and diminished cell migration. We propose a novel force-controlled molecular switch that refines the mechanism of talin-mediated focal adhesion activation, providing negative feedback during focal adhesion maturation. The broader effects of this talin-mediated mechanism need to be elucidated, as it might regulate multiple cellular events.
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9.2
作者：
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DOI：
10.1083/jcb.201510012
发表时间：
2016-05-09
期刊：
The Journal of cell biology
影响因子：
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作者：
Kumar A;Ouyang M;Van den Dries K;McGhee EJ;Tanaka K;Anderson MD;Groisman A;Goult BT;Anderson KI;Schwartz MA
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