A novel membrane-dependent on/off switch mechanism of talin FERM domain at sites of cell adhesion
A novel membrane-dependent on/off switch mechanism of talin FERM domain at sites of cell adhesion
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DOI：
10.1038/cr.2012.97
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发表时间：
2012-11-01
期刊：
影响因子：
44.1
通讯作者：
Qin, Jun
中科院分区：
文献类型：
--
作者：
Song, Xianqiang;Yang, Jun;Qin, Jun
异源二聚体（α/β）整合素跨膜受体的胞质蛋白塔林的激活是至关重要的调节多种细胞粘附依赖性的过程，包括血液凝固，组织重塑，和癌症转移。这一过程是由Talin（Talin-FERM）的N-末端FERM（四点一蛋白/ezrin/radixin/moesin）结构域与内膜表面和整合素β胞质尾区的同时结合触发的，但这些结合事件是如何时空调节的仍然不清楚。在这里，我们报告的晶体结构的休眠塔林，揭示了C-末端塔林杆段（塔林RS）自我面具的关键整合素结合位点塔林FERM通过一个大的接口。出乎意料的是，该结构还揭示了talin-RS上的明显带负电荷的表面，其静电阻碍了talin-FERM与膜的结合。这样一个双重抑制拓扑结构的塔林是一致的生化和功能的数据，但显着不同，从以前的模型。我们发现，在富集磷脂酰肌醇-4，5-二磷酸（PIP 2）-一个已知的塔林激活剂，膜强烈吸引带正电荷的表面塔林-FERM，同时排斥带负电荷的表面塔林-RS。这种静电“推拉”过程促进了talin-FERM的双重抑制的缓解，这不同于传统PIP 2诱导的FERM结构域激活的经典“空间冲突”模型。因此，这些数据揭示了一种新型的膜依赖性FERM结构域的调节，并说明它是如何介导的塔林开/关开关，以调节整合素跨膜信号和细胞粘附。
The activation of heterodimeric (alpha/beta) integrin transmembrane receptors by cytosolic protein talin is crucial for regulating diverse cell-adhesion-dependent processes, including blood coagulation, tissue remodeling, and cancer metastasis. This process is triggered by the coincident binding of N-terminal FERM (four-point-one-protein/ezrin/radixin/moesin) domain of talin (talin-FERM) to the inner membrane surface and integrin beta cytoplasmic tail, but how these binding events are spatiotemporally regulated remains obscure. Here we report the crystal structure of a dormant talin, revealing how a C-terminal talin rod segment (talin-RS) self-masks a key integrin-binding site on talin-FERM via a large interface. Unexpectedly, the structure also reveals a distinct negatively charged surface on talin-RS that electrostatically hinders the talin-FERM binding to the membrane. Such a dual inhibitory topology for talin is consistent with the biochemical and functional data, but differs significantly from a previous model. We show that upon enrichment with phosphotidylinositol-4,5-bisphosphate (PIP2) - a known talin activator, membrane strongly attracts a positively charged surface on talin-FERM and simultaneously repels the negatively charged surface on talin-RS. Such an electrostatic "pull-push" process promotes the relief of the dual inhibition of talin-FERM, which differs from the classic "steric clash" model for conventional PIP2-induced FERM domain activation. These data therefore unravel a new type of membrane-dependent FERM domain regulation and illustrate how it mediates the talin on/off switches to regulate integrin transmembrane signaling and cell adhesion.