Integrin extension enables ultrasensitive regulation by cytoskeletal force
Integrin extension enables ultrasensitive regulation by cytoskeletal force
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DOI：
10.1073/pnas.1704171114
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发表时间：
2017-05-02
影响因子：
11.1
通讯作者：
Springer, Timothy A.
中科院分区：
文献类型：
--
作者：
Li, Jing;Springer, Timothy A.
整合素在活化后经历大规模构象变化。驱动整合素激活的信号事件之前已经在概念上进行了讨论，但没有定量讨论。在这里，最近测量的内在配体结合亲和力和自由能的细胞表面上的每个整合素的构象状态，连同构象变化的长度尺度，被用来定量比较模型的激活。我们研究是否结合的细胞骨架衔接整合素胞质结构域是足够的激活或是否施加张力的肌动蛋白细胞骨架跨整合素-配体复合物也是必需的。我们发现，只有接头结合和细胞骨架力的组合提供了超灵敏的调节。此外，通过力的开关样激活取决于整联蛋白延伸中大于130埃的长度尺度变化，其被很好地定制以匹配非活性（闭合）和活性（延伸-开放）构象之间的自由能差异。整合素延伸中的长度尺度和能量成本使得能够在低pN范围内通过力激活，并且似乎是使细胞粘附通过整合素与细胞骨架动力学协调的关键专业化。
Integrins undergo large-scale conformational changes upon activation. Signaling events driving integrin activation have previously been discussed conceptually, but not quantitatively. Here, recent measurements of the intrinsic ligand-binding affinity and free energy of each integrin conformational state on the cell surface, together with the length scales of conformational change, are used to quantitatively compare models of activation. We examine whether binding of cytoskeletal adaptors to integrin cytoplasmic domains is sufficient for activation or whether exertion of tensile force by the actin cytoskeleton across the integrin-ligand complex is also required. We find that only the combination of adaptor binding and cytoskeletal force provides ultrasensitive regulation. Moreover, switch-like activation by force depends on the large, >130 angstrom length-scale change in integrin extension, which is well tailored to match the free-energy difference between the inactive (bent-closed) and active (extended-open) conformations. The length scale and energy cost in integrin extension enable activation by force in the low pN range and appear to be the key specializations that enable cell adhesion through integrins to be coordinated with cytoskeletal dynamics.