Department of Molecular Cardiology, Lerner Research Institute, Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, OH 44195, USA.
Mol Cell. 2009 Dec 11;36(5):819-30. doi: 10.1016/j.molcel.2009.11.028.
Integrin-linked kinase (ILK) plays a pivotal role in connecting transmembrane receptor integrin to the actin cytoskeleton and thereby regulating diverse cell-adhesion-dependent processes. The kinase domain (KD) of ILK is indispensable for its function, but the underlying molecular basis remains enigmatic. Here we present the crystal structure of the ILK KD bound to its cytoskeletal regulator, the C-terminal calponin homology domain of alpha-parvin. While maintaining a canonical kinase fold, the ILK KD displays a striking pseudoactive site conformation. We show that rather than performing the kinase function, this conformation specifically recognizes alpha-parvin for promoting effective assembly of ILK into focal adhesions. The alpha-parvin-bound ILK KD can simultaneously engage integrin beta cytoplasmic tails. These results thus define ILK as a distinct pseudokinase that mechanically couples integrin and alpha-parvin for mediating cell adhesion. They also highlight functional diversity of the kinase fold and its "active" site in mediating many biological processes.
整合素连接激酶（ILK）在连接跨膜受体整合素和肌动蛋白细胞骨架方面发挥着关键作用，从而调节多种细胞黏附依赖性过程。ILK 的激酶结构域（KD）对于其功能是不可或缺的，但潜在的分子基础仍然是个谜。在这里，我们展示了与细胞骨架调节剂α-辅肌动蛋白的 C 端钙调蛋白同源结构域结合的 ILK KD 的晶体结构。虽然保持了典型的激酶折叠，但 ILK KD 显示出惊人的伪活性位点构象。我们表明，这种构象不是执行激酶功能，而是专门识别 α-辅肌动蛋白，以促进 ILK 有效地组装到黏附斑中。结合 α-辅肌动蛋白的 ILK KD 可以同时与整合素β胞质尾巴结合。因此，这些结果将 ILK 定义为一种独特的拟激酶，它通过机械偶联整合素和α-辅肌动蛋白来介导细胞黏附。它们还突出了激酶折叠及其“活性”位点在介导许多生物学过程中的功能多样性。
