Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, United States.
California Institute for Quantitative Biosciences, University of California, Berkeley, Berkeley, United States.
Elife. 2016 Mar 7;5:e13405. doi: 10.7554/eLife.13405.
Activation triggers the exchange of subunits in Ca(2+)/calmodulin-dependent protein kinase II (CaMKII), an oligomeric enzyme that is critical for learning, memory, and cardiac function. The mechanism by which subunit exchange occurs remains elusive. We show that the human CaMKII holoenzyme exists in dodecameric and tetradecameric forms, and that the calmodulin (CaM)-binding element of CaMKII can bind to the hub of the holoenzyme and destabilize it to release dimers. The structures of CaMKII from two distantly diverged organisms suggest that the CaM-binding element of activated CaMKII acts as a wedge by docking at intersubunit interfaces in the hub. This converts the hub into a spiral form that can release or gain CaMKII dimers. Our data reveal a three-way competition for the CaM-binding element, whereby phosphorylation biases it towards the hub interface, away from the kinase domain and calmodulin, thus unlocking the ability of activated CaMKII holoenzymes to exchange dimers with unactivated ones.
激活会触发钙调蛋白依赖性蛋白激酶 II（CaMKII）亚基的交换，这种寡聚酶对于学习、记忆和心脏功能至关重要。亚基交换发生的机制仍然难以捉摸。我们表明，人 CaMKII 全酶以十二聚体和十四聚体的形式存在，并且 CaMKII 的钙调蛋白（CaM）结合元件可以结合到全酶的中心，并使其不稳定以释放二聚体。来自两种差异很大的生物体的 CaMKII 的结构表明，激活的 CaMKII 的 CaM 结合元件通过停靠在中心的亚基界面充当楔子。这将中心转换成可以释放或获得 CaMKII 二聚体的螺旋形式。我们的数据揭示了 CaM 结合元件的三向竞争，其中磷酸化使它偏向于中心界面，远离激酶结构域和钙调蛋白，从而释放激活的 CaMKII 全酶与未激活的全酶交换二聚体的能力。
