Division of Oncology, Department of Clinical Sciences, Lund University, Lund, Sweden.
Niels Bohr Institute, University of Copenhagen, Copenhagen, Denmark.
Life Sci Alliance. 2023 Jul 18;6(10). doi: 10.26508/lsa.202301898. Print 2023 Oct.
Specificity of cellular responses to distinct cues from the ECM requires precise and sensitive decoding of physical information. However, how known mechanisms of mechanosensing like force-dependent catch bonds and conformational changes in FA proteins can confer that this sensitivity is not known. Using polarization microscopy and computational modeling, we identify dynamic changes in an orientational order of FA proteins as a molecular organizational mechanism that can fine-tune cell sensitivity to the ECM. We find that αV integrins and F-actin show precise changes in the orientational order in an ECM-mediated integrin activation-dependent manner. These changes are sensitive to ECM density and are regulated independent of myosin-II activity though contractility can enhance this sensitivity. A molecular-clutch model demonstrates that the orientational order of integrin-ECM binding coupled to directional catch bonds can capture cellular responses to changes in ECM density. This mechanism also captures decoupling of ECM density sensing from stiffness sensing thus elucidating specificity. Taken together, our results suggest relative geometric organization of FA molecules as an important molecular architectural feature and regulator of mechanotransduction.
细胞对细胞外基质中不同信号的特异性反应需要精确和敏感地解码物理信息。然而，目前已知的机械传感机制，如力依赖性捕获键和 FA 蛋白构象变化，如何能赋予这种敏感性尚不清楚。我们使用偏光显微镜和计算建模，确定了 FA 蛋白的取向有序性的动态变化，作为一种分子组织机制，可以精细调节细胞对细胞外基质的敏感性。我们发现 αV 整合素和 F-肌动蛋白在细胞外基质介导的整合素激活依赖性方式下表现出取向有序性的精确变化。这些变化对细胞外基质密度敏感，并且独立于肌球蛋白 II 活性调节，尽管收缩性可以增强这种敏感性。分子离合器模型表明，与定向捕获键偶联的整合素-细胞外基质结合的取向有序性可以捕获细胞对细胞外基质密度变化的反应。该机制还可以将细胞外基质密度传感与刚度传感解耦，从而阐明特异性。总之，我们的结果表明，FA 分子的相对几何组织作为机械转导的一个重要的分子结构特征和调节剂。
