Puklin-Faucher Eileen, Gao Mu, Schulten Klaus, Vogel Viola
Department of Materials, Swiss Federal Institute of Technology in Zurich (ETH Zurich), CH-8093 Zurich, Switzerland.
J Cell Biol. 2006 Oct 23;175(2):349-60. doi: 10.1083/jcb.200602071.
How the integrin head transitions to the high-affinity conformation is debated. Although experiments link activation with the opening of the hinge angle between the betaA and hybrid domains in the ligand-binding headpiece, this hinge is closed in the liganded alpha(v)beta3 integrin crystal structure. We replaced the RGD peptide ligand of this structure with the 10th type III fibronectin module (FnIII10) and discovered through molecular dynamics (MD) equilibrations that when the conformational constraints of the leg domains are lifted, the betaA/hybrid hinge opens spontaneously. Together with additional equilibrations on the same nanosecond timescale in which small structural variations impeded hinge-angle opening, these simulations allowed us to identify the allosteric pathway along which ligand-induced strain propagates via elastic distortions of the alpha1 helix to the betaA/hybrid domain hinge. Finally, we show with steered MD how force accelerates hinge-angle opening along the same allosteric pathway. Together with available experimental data, these predictions provide a novel framework for understanding integrin activation.
整联蛋白头部如何转变为高亲和力构象仍存在争议。尽管实验表明激活与配体结合头部中βA和杂合结构域之间铰链角的打开有关，但在结合配体的α(v)β3整联蛋白晶体结构中，这个铰链是关闭的。我们用第10型III型纤连蛋白模块（FnIII10）取代了该结构的RGD肽配体，并通过分子动力学（MD）平衡发现，当腿部结构域的构象限制解除时，βA/杂合铰链会自发打开。在相同的纳秒时间尺度上进行的额外平衡实验中，小的结构变化阻碍了铰链角的打开，这些模拟使我们能够确定变构途径，配体诱导的应变通过α1螺旋的弹性变形沿着该途径传播到βA/杂合结构域铰链。最后，我们用引导分子动力学展示了力如何沿着相同的变构途径加速铰链角的打开。结合现有的实验数据，这些预测为理解整联蛋白激活提供了一个新的框架。
