Pan Di, Song Yuhua
Department of Biomedical Engineering, The University of Alabama at Birmingham, 803 Shelby Interdisciplinary Biomedical Research Building, 1825 University Boulevard, Birmingham, AL 35294, USA.
Mol Cell Biomech. 2011 Sep;8(3):233-52.
Cytoskeletal restraints affect force-regulated integrin function in cell adhesion. However, the structural and molecular basis underlying the effect of cytoskeletal restraints on beta1 integrin binding to fibronectin is still largely unknown. In this study, we used steered molecular dynamics simulations to investigate the changes in glycosylated beta1 integrin-fibronectin binding and in conformation and structure of the glycosylated beta1 I-like domain-FN-III9-10 complex caused by altered restraints applied to beta1 I-like domain. The results revealed that imposition of the increased constraints on beta1 integrin increased resistance to force-induced dissociation of the beta1 I-like domain-fibronectin complex. Specifically, the increased constraints enhanced resistance to relative conformational changes in the RGD-synergy site in fibronectin, increased the conformational stability of fibronectin, and prevented losses in hydrogen bond occupancy of each beta-strand pair in FN-III10 resulting from external force. The increased constraints also resulted in an increase in correlated motion between residues in the beta1 I-like domain, which may directly affect the interaction of beta1 integrin with fibronectin. Results from this study provide molecular and structural insights into the effects of altered restraints in beta1 integrin on the interaction between glycosylated beta1 Integrin and fibronectin and its induced cell adhesion.
细胞骨架限制影响细胞黏附中力调节的整合素功能。然而，细胞骨架限制对β1整合素与纤连蛋白结合作用的结构和分子基础仍 largely unknown。在本研究中，我们使用引导分子动力学模拟来研究对β1 I样结构域施加改变的限制所导致的糖基化β1整合素-纤连蛋白结合以及糖基化β1 I样结构域-FN-III9-10复合物的构象和结构变化。结果表明，对β1整合素施加增加的限制会增加β1 I样结构域-纤连蛋白复合物对力诱导解离的抵抗力。具体而言，增加的限制增强了对纤连蛋白中RGD协同位点相对构象变化的抵抗力，增加了纤连蛋白的构象稳定性，并防止了外力导致的FN-III10中每个β链对氢键占有率的损失。增加的限制还导致β1 I样结构域中残基之间的相关运动增加，这可能直接影响β1整合素与纤连蛋白的相互作用。本研究结果为β1整合素中改变的限制对糖基化β1整合素与纤连蛋白之间相互作用及其诱导的细胞黏附的影响提供了分子和结构上的见解。
