Structure of the CaMKIIdelta/calmodulin complex reveals the molecular mechanism of CaMKII kinase activation.
Structure of the CaMKIIdelta/calmodulin complex reveals the molecular mechanism of CaMKII kinase activation.
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DOI：
10.1371/journal.pbio.1000426
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发表时间：
2010-07-27
期刊：
影响因子：
9.8
通讯作者：
Knapp S
中科院分区：
文献类型：
--
作者：
Rellos P;Pike AC;Niesen FH;Salah E;Lee WH;von Delft F;Knapp S
结构和生物物理研究揭示了对细胞学习和记忆很重要的CaMKII激酶是如何通过Ca2+/钙调蛋白的结合而开启的。长时程增强（LTP）是神经元间交流的一种持久增强，被认为是学习和记忆的主要细胞机制。LTP触发高频钙脉冲，导致钙/钙调素（CaM）依赖性激酶II （CaMKII）的激活。CaMKII作为一个分子开关，因为它在恢复到基础钙水平后长时间保持活性，这是CaMKII功能所需的独特性质。在这里，我们描述了人类CaMKIIδ/Ca2+/CaM复合物的晶体结构，所有四个人类CaMKII催化结构域在其自抑制状态下的结构，以及人类CaMKII寡聚化结构域在其四聚体和生理十二聚体状态下的结构。所有四种自抑制的人类camkii在确定的晶体结构中均为单体，但在溶液中相关性较弱。在CaMKIIδ/Ca2+/CaM复合物中，抑制区采用扩展构象，并与相邻的催化结构域T287定位到相互作用原聚体的活性位点。与自抑制CaMKII结构的比较表明，钙调素的结合导致活性位点残基重排为适合ATP结合的构象，并导致自抑制螺旋的结合槽被螺旋αD关闭。这些结构数据以及生物物理相互作用研究揭示了钙调素激活CaMKII的机制，并解释了这两种重要信号分子的许多独特调控特性。本文也可以被视为增强版，其中文章的文本与交互式3d表示和动画过渡相结合。请注意，需要一个web插件来访问这个增强的功能。关于安装和使用Web插件的说明可在文本S1中找到。CaMKII酶通过磷酸化调控信号转导通路，传递细胞内释放的钙离子（Ca2+）信号：Ca2+首先与小调节蛋白CaM结合；然后这个Ca2+/CaM复合物结合并激活激酶，使细胞中的其他蛋白质磷酸化。由于CaMKs在快速Ca2+脉冲下降后很长一段时间仍保持活性，它们作为分子开关，根据Ca2+水平打开或关闭关键的细胞功能。这种酶的多功能CaMKII形式——人类有四种——在许多过程中都很重要，包括神经元的信号传导和心率的控制。它们在大脑中尤其丰富，可能在记忆中起作用。CaMKII形成一个特别大的十二聚体复合体。在这里，我们描述了这四个人类CaMKII催化结构域在其自抑制状态下的晶体结构，CaMKII与Ca2+/CaM的复合物，以及在其生理十二聚体状态和十四聚体状态下的寡聚化结构域（介导复合物形成的蛋白质的一部分）的结构。将这一庞大的结构数据与生物物理研究进行详细比较，使我们能够更好地理解CaM激活CaMKII的结构机制，并解释这些必需酶的许多复杂调控特征。
Structural and biophysical studies reveal how CaMKII kinases, which are important for cellular learning and memory, are switched on by binding of Ca2+/calmodulin. Long-term potentiation (LTP), a long-lasting enhancement in communication between neurons, is considered to be the major cellular mechanism underlying learning and memory. LTP triggers high-frequency calcium pulses that result in the activation of Calcium/Calmodulin (CaM)-dependent kinase II (CaMKII). CaMKII acts as a molecular switch because it remains active for a long time after the return to basal calcium levels, which is a unique property required for CaMKII function. Here we describe the crystal structure of the human CaMKIIδ/Ca2+/CaM complex, structures of all four human CaMKII catalytic domains in their autoinhibited states, as well as structures of human CaMKII oligomerization domains in their tetradecameric and physiological dodecameric states. All four autoinhibited human CaMKIIs were monomeric in the determined crystal structures but associated weakly in solution. In the CaMKIIδ/Ca2+/CaM complex, the inhibitory region adopted an extended conformation and interacted with an adjacent catalytic domain positioning T287 into the active site of the interacting protomer. Comparisons with autoinhibited CaMKII structures showed that binding of calmodulin leads to the rearrangement of residues in the active site to a conformation suitable for ATP binding and to the closure of the binding groove for the autoinhibitory helix by helix αD. The structural data, together with biophysical interaction studies, reveals the mechanism of CaMKII activation by calmodulin and explains many of the unique regulatory properties of these two essential signaling molecules. This article can also be viewed as an enhanced version in which the text of the article is integrated with interactive 3-D representations and animated transitions. Please note that a web plugin is required to access this enhanced functionality. Instructions for the installation and use of the Web plugin are available in Text S1. CaMKII enzymes transmit calcium ion (Ca2+) signals released inside the cell by regulating signal transduction pathways through phosphorylation: Ca2+ first binds to the small regulatory protein CaM; this Ca2+/CaM complex then binds to and activates the kinase, which phosphorylates other proteins in the cell. Since CaMKs remain active long after rapid Ca2+ pulses have dropped they function as molecular switches that turn on or off crucial cell functions in response to Ca2+ levels. The multifunctional CaMKII forms of this enzyme – of which there are four in human – are important in many processes including signaling in neurons and controlling of the heart rate. They are particularly abundant in the brain where they probably play a role in memory. CaMKII forms an exceptionally large, dodecameric complex. Here, we describe the crystal structure of this complex for each of the four human CaMKII catalytic domains in their autoinhibited states, a complex of CaMKII with Ca2+/CaM, as well as the structure of the oligomerization domain (the part of the protein that mediates complex formation) in its physiological dodecameric state and in a tetradecameric state. Detailed comparison of this large body of structural data together with biophysical studies has allowed us to better understand the structural mechanisms of CaMKII activation by CaM and to explain many of the complex regulatory features of these essential enzymes.
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