Kim Eun Young, Rumpf Christine H, Fujiwara Yuichiro, Cooley Elizabeth S, Van Petegem Filip, Minor Daniel L
Cardiovascular Research Institute, Department of Biochemistry and Biophysics, California Institute for Quantitative Biosciences, University of California, San Francisco, CA 94158-2330, USA.
Structure. 2008 Oct 8;16(10):1455-67. doi: 10.1016/j.str.2008.07.010.
Calcium influx drives two opposing voltage-activated calcium channel (Ca(V)) self-modulatory processes: calcium-dependent inactivation (CDI) and calcium-dependent facilitation (CDF). Specific Ca(2+)/calmodulin (Ca(2+)/CaM) lobes produce CDI and CDF through interactions with the Ca(V)alpha(1) subunit IQ domain. Curiously, Ca(2+)/CaM lobe modulation polarity appears inverted between Ca(V)1s and Ca(V)2s. Here, we present crystal structures of Ca(V)2.1, Ca(V)2.2, and Ca(V)2.3 Ca(2+)/CaM-IQ domain complexes. All display binding orientations opposite to Ca(V)1.2 with a physical reversal of the CaM lobe positions relative to the IQ alpha-helix. Titration calorimetry reveals lobe competition for a high-affinity site common to Ca(V)1 and Ca(V)2 IQ domains that is occupied by the CDI lobe in the structures. Electrophysiological experiments demonstrate that the N-terminal Ca(V)2 Ca(2+)/C-lobe anchors affect CDF. Together, the data unveil the remarkable structural plasticity at the heart of Ca(V) feedback modulation and indicate that Ca(V)1 and Ca(V)2 IQ domains bear a dedicated CDF site that exchanges Ca(2+)/CaM lobe occupants.
钙内流驱动两种相反的电压激活钙通道（Ca(V)）自我调节过程：钙依赖性失活（CDI）和钙依赖性易化（CDF）。特定的Ca(2+)/钙调蛋白（Ca(2+)/CaM）叶通过与Ca(V)α(1)亚基IQ结构域相互作用产生CDI和CDF。奇怪的是，Ca(2+)/CaM叶调节极性在Ca(V)1和Ca(V)2之间似乎是相反的。在这里，我们展示了Ca(V)2.1、Ca(V)2.2和Ca(V)2.3的Ca(2+)/CaM-IQ结构域复合物的晶体结构。所有结构都显示出与Ca(V)1.2相反的结合方向，CaM叶相对于IQα螺旋的位置发生了物理反转。滴定热分析法揭示了叶对Ca(V)1和Ca(V)2 IQ结构域共有的高亲和力位点的竞争，该位点在结构中被CDI叶占据。电生理实验表明，N端Ca(V)2 Ca(2+)/C叶锚定影响CDF。总之，这些数据揭示了Ca(V)反馈调节核心的显著结构可塑性，并表明Ca(V)1和Ca(V)2 IQ结构域有一个专门的CDF位点，该位点可交换Ca(2+)/CaM叶占据者。
