Vinculin Activation Is Necessary for Complete Talin Binding
Vinculin Activation Is Necessary for Complete Talin Binding
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DOI：
10.1016/j.bpj.2010.11.024
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发表时间：
2011-01-19
影响因子：
3.4
通讯作者：
Mofrad, Mohammad R. K.
中科院分区：
文献类型：
--
作者：
Golji, Javad;Lam, Johnny;Mofrad, Mohammad R. K.
焦点粘连在许多细胞过程中起着至关重要的作用，这些过程涉及细胞内信号转导和与细胞环境的机械相互作用。这些灶性粘连的生长和加强依赖于talin和vinculin之间的相互作用。这项研究调查了这种相互作用以及纽蛋白的激活是如何影响它的。用分子动力学方法模拟了TALIN的纽蛋白结合位点(VBS)和纽蛋白的结构域1(D1)在纽蛋白活化前后的相互作用。激活前VBS与纽蛋白结合的模拟表明，纽蛋白尾部与D1的接近阻止了D1的螺旋运动，从而阻止了VBS的结合。相反，VBS与激活的纽蛋白的相互作用表明VBS有可能完全插入到D1中。在对VBS不能完全结合的激活和自抑制纽蛋白的模拟中，VBS与D1中的表面残基显示出显著的疏水相互作用。这些相互作用将VBS连接到D1，即使它没有正确插入到疏水核心中。综上所述，这些模拟表明VBS通过以下机制与纽蛋白结合：1)，VBS通过表面疏水作用与D1连接；2)纽蛋白被激活，D1从纽蛋白尾部移开；3)D1中的螺旋发生构象变化以允许VBS结合；以及4)VBS插入到D1的疏水核心中。
Focal adhesions are critical to a number of cellular processes that involve nnechanotransduction and mechanical interaction with the cellular environment. The growth and strengthening of these focal adhesions is dependent on the interaction between talin and vinculin. This study investigates said interaction and how vinculin activation influences it. Using molecular dynamics, the interaction between talin's vinculin binding site (VBS) and vinculin's domain 1 (D1) is simulated both before and after vinculin activation. The simulations of VBS binding to vinculin before activation suggest the proximity of the vinculin tail to D1 prevents helical movement in D1 and thus prevents binding of VBS. In contrast, interaction of VBS with activated vinculin shows the possibility of complete VBS insertion into D1. In the simulations of both activated and autoinhibited vinculin where VBS fails to fully bind, VBS demonstrates significant hydrophobic interaction with surface residues in D1. These interactions link VBS to D1 even without its proper insertion into the hydrophobic core. Together these simulations suggest VBS binds to vinculin with the following mechanism: 1), VBS links to D1 via surface hydrophobic interactions; 2), vinculin undergoes activation and D1 is moved away from the vinculin tail; 3), helices in D1 undergo conformational change to allow VBS binding; and 4), VBS inserts itself into the hydrophobic core of D1.