Molecular Cell Biomechanics Laboratory, Department of Bioengineering, University of California, Berkeley, CA, USA.
Biophys J. 2012 Nov 21;103(10):2050-9. doi: 10.1016/j.bpj.2012.08.044. Epub 2012 Nov 20.
The mechanisms by which living cells respond to mechanical stimuli are not yet fully understood. It has been suggested that mechanosensing proteins play an important role in mechanotransduction because their binding affinities are directly affected by the external stress. α-Actinin is an actin cross-linker and may act as a mechanosensor in adhesion sites. Its interaction with vinculin is suggested to be mechanically regulated. In this study, the free energy of activation is explored using the umbrella sampling method. An activation trajectory is generated in which α-actinin's vinculin-binding site swings out of the rod domain, leading to approximately an 8 kcal/mol free energy release. The activation trajectory reveals several local and global conformational changes along the activation pathway accompanied by the breakage of a number of key interactions stabilizing the inhibited structure. These results may shed light on the role of α-actinin in cellular mechanotransduction and focal adhesion formation.
活细胞对机械刺激做出响应的机制尚不完全清楚。有人提出，机械感受器蛋白在机械转导中起着重要作用，因为它们的结合亲和力直接受到外部压力的影响。α-辅肌动蛋白是一种肌动蛋白交联蛋白，在黏附位点可能作为机械感受器。其与衔接蛋白的相互作用被认为受到机械调节。在这项研究中，使用伞形采样方法探索了活化自由能。生成了一条激活轨迹，其中α-辅肌动蛋白的衔接蛋白结合位点从杆状结构域中摆动出来，导致大约 8 千卡/摩尔的自由能释放。激活轨迹揭示了沿着激活途径的几个局部和全局构象变化，伴随着破坏许多稳定抑制结构的关键相互作用。这些结果可能有助于阐明α-辅肌动蛋白在细胞机械转导和黏附斑形成中的作用。
