RIAM and vinculin binding to talin are mutually exclusive and regulate adhesion assembly and turnover.
RIAM and vinculin binding to talin are mutually exclusive and regulate adhesion assembly and turnover.
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DOI：
10.1074/jbc.m112.438119
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发表时间：
2013-03-22
期刊：
影响因子：
--
通讯作者：
Barsukov IL
中科院分区：
文献类型：
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作者：
Goult BT;Zacharchenko T;Bate N;Tsang R;Hey F;Gingras AR;Elliott PR;Roberts GCK;Ballestrem C;Critchley DR;Barsukov IL
背景：Talin介导依赖Riam的整合素激活，并与纽蛋白结合，从而稳定粘连。结果：结构和生化数据显示，纽蛋白抑制RiAM与Talin杆的致密N-末端区域的结合，该区域是焦点黏附组装所必需的区域。结论：Talin·riam复合体激活前沿的整合素，Talin·vinculin促进黏附成熟。意义：塔林改变伴侣，以回应力量诱导的构象变化。Talin激活整合素，将其与F-肌动蛋白偶联，并将其招募到局部粘连(FA)中。在这里，我们报告了Talin棒的结构特征：13个螺旋束(R1-R13)组织成一个紧凑的四螺旋束簇(R2-R4)，在一个五螺旋束的线性链中。其中九束含有纽蛋白结合位点(VBS)；R2R3是非典型的，每束含有两个VBS。Talin R2R3还与RIAM协同结合，RIAM是一种参与整合素激活的Rap1效应器。生化和结构数据表明，纽蛋白和Riam与R2R3的结合是相互排斥的。此外，纽蛋白结合需要结构域展开，而RIAM结合折叠的R2R3双结构域。在细胞中，RIAM在前沿的新生粘连中丰富，而纽蛋白在FAs中丰富。我们提出了一个模型，在这个模型中，RIAM与R2R3结合，最初将talin招募到膜上，在那里它激活整合素。当talin与F-肌动蛋白结合时，施加在R2R3上的力破坏Riam结合并暴露VBS，VBS招募vinculin来稳定复合体。
Background: Talin mediates RIAM-dependent integrin activation and binds vinculin, which stabilizes adhesions. Results: Structural and biochemical data show that vinculin inhibits RIAM binding to the compact N-terminal region of the talin rod, a region essential for focal adhesion assembly. Conclusion: Talin·RIAM complexes activate integrins at the leading edge, whereas talin·vinculin promotes adhesion maturation. Significance: Talin changes partners in response to force-induced conformational change. Talin activates integrins, couples them to F-actin, and recruits vinculin to focal adhesions (FAs). Here, we report the structural characterization of the talin rod: 13 helical bundles (R1–R13) organized into a compact cluster of four-helix bundles (R2–R4) within a linear chain of five-helix bundles. Nine of the bundles contain vinculin-binding sites (VBS); R2R3 are atypical, with each containing two VBS. Talin R2R3 also binds synergistically to RIAM, a Rap1 effector involved in integrin activation. Biochemical and structural data show that vinculin and RIAM binding to R2R3 is mutually exclusive. Moreover, vinculin binding requires domain unfolding, whereas RIAM binds the folded R2R3 double domain. In cells, RIAM is enriched in nascent adhesions at the leading edge whereas vinculin is enriched in FAs. We propose a model in which RIAM binding to R2R3 initially recruits talin to membranes where it activates integrins. As talin engages F-actin, force exerted on R2R3 disrupts RIAM binding and exposes the VBS, which recruit vinculin to stabilize the complex.