Center for Theoretical Biological Physics, Rice University, Houston, TX 77005.
Department of Neurobiology and Anatomy, The University of Texas Health Science Center at Houston McGovern Medical School, Houston, TX 77030.
Proc Natl Acad Sci U S A. 2019 Sep 17;116(38):18937-18942. doi: 10.1073/pnas.1911452116. Epub 2019 Aug 27.
Calcium/calmodulin-dependent kinase II (CaMKII) plays a key role in the plasticity of dendritic spines. Calcium signals cause calcium-calmodulin to activate CaMKII, which leads to remodeling of the actin filament (F-actin) network in the spine. We elucidate the mechanism of the remodeling by combining computer simulations with protein array experiments and electron microscopic imaging, to arrive at a structural model for the dodecameric complex of CaMKII with F-actin. The binding interface involves multiple domains of CaMKII. This structure explains the architecture of the micrometer-scale CaMKII/F-actin bundles arising from the multivalence of CaMKII. We also show that the regulatory domain of CaMKII may bind either calmodulin or F-actin, but not both. This frustration, along with the multipartite nature of the binding interface, allows calmodulin transiently to strip CaMKII from actin assemblies so that they can reorganize. This observation therefore provides a simple mechanism by which the structural dynamics of CaMKII establishes the link between calcium signaling and the morphological plasticity of dendritic spines.
钙/钙调蛋白依赖性激酶 II（CaMKII）在树突棘的可塑性中发挥关键作用。钙信号导致钙-钙调蛋白激活 CaMKII，从而导致棘突中肌动蛋白丝（F-actin）网络的重塑。我们通过将计算机模拟与蛋白质阵列实验和电子显微镜成像相结合，阐明了重塑的机制，得出了 CaMKII 与 F-actin 的十二聚体复合物的结构模型。结合界面涉及 CaMKII 的多个结构域。该结构解释了源自 CaMKII 多价性的微米尺度 CaMKII/F-actin 束的结构。我们还表明，CaMKII 的调节结构域可以结合钙调蛋白或 F-actin，但不能同时结合两者。这种挫折以及结合界面的多部分性质允许钙调蛋白瞬时从肌动蛋白组装体上剥离 CaMKII，从而使它们能够重新组织。因此，这一观察结果提供了一种简单的机制，即 CaMKII 的结构动力学将钙信号与树突棘的形态可塑性联系起来。
