Integrin-based mechanosensing through conformational deformation.
Integrin-based mechanosensing through conformational deformation.
复制标题
通过构象变形进行基于整合素的机械传感。
DOI：
10.1016/j.bpj.2021.09.010
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发表时间：
2021
影响因子：
3.4
通讯作者：
Schwartz,MartinA
中科院分区：
文献类型：
--
作者：
Driscoll,TristanP;Bidone,TamaraC;Ahn,SangJoon;Yu,Alvin;Groisman,Alexander;Voth,GregoryA;Schwartz,MartinA
整合素从低亲和力状态到高亲和力状态的转化，被称为活化，在包括免疫、止血、血管生成和胚胎发育在内的生物过程中是重要的。整合素的激活受到从封闭、低亲和力状态到开放、高亲和力状态的大规模构象转变的调节。尽管有人认为底物刚度改变了整合素的构象平衡并控制了其解结合，但在这里，我们讨论了整合素构象激活在细胞机械传感中的作用。整合素α v β3野生型与激活突变体的比较表明，激活突变体在较低刚度下使细胞扩散、黏附激酶活化、牵引应力和对talin施加的力向高刚度值偏移。虽然所有激活的整合素突变体对可溶性配体的结合亲和力相当，但β3 S243E突变体在机械响应方面表现出最强的变化。为了理解这种行为，我们使用了来自分子水平信息的粗粒度计算模型。模型预测野生型整合素α v β3在外力作用下发生位移，激活突变使所需的力向较低的值移动，其中S243E的作用最强。因此，细胞刚度感知与计算力对整合素构象的影响相关。总之，这些数据确定了力诱导整合素构象变形在细胞机械传感中的作用。
Conversion of integrins from low to high affinity states, termed activation, is important in biological processes, including immunity, hemostasis, angiogenesis, and embryonic development. Integrin activation is regulated by large-scale conformational transitions from closed, low affinity states to open, high affinity states. Although it has been suggested that substrate stiffness shifts the conformational equilibrium of integrin and governs its unbinding, here, we address the role of integrin conformational activation in cellular mechanosensing. Comparison of wild-type versus activating mutants of integrinαVβ3 show that activating mutants shift cell spreading, focal adhesion kinase activation, traction stress, and force on talin toward high stiffness values at lower stiffness. Although all activated integrin mutants showed equivalent binding affinity for soluble ligands, theβ3 S243E mutant showed the strongest shift in mechanical responses. To understand this behavior, we used coarse-grained computational models derived from molecular level information. The models predicted that wild-type integrinαVβ3 displaces under force and that activating mutations shift the required force toward lower values, with S243E showing the strongest effect. Cellular stiffness sensing thus correlates with computed effects of force on integrin conformation. Together, these data identify a role for force-induced integrin conformational deformation in cellular mechanosensing.