Department of Pharmacology, School of Medicine, Case Western Reserve University, Cleveland, OH 44106-4965, USA.
Structure. 2010 Jan 13;18(1):116-26. doi: 10.1016/j.str.2009.11.008.
Neuronal Ca(2+) sensors (NCS) are high-affinity Ca(2+)-binding proteins critical for regulating a vast range of physiological processes. Guanylate cyclase-activating proteins (GCAPs) are members of the NCS family responsible for activating retinal guanylate cyclases (GCs) at low Ca(2+) concentrations, triggering synthesis of cGMP and recovery of photoreceptor cells to the dark-adapted state. Here we use amide hydrogen-deuterium exchange and radiolytic labeling, and molecular dynamics simulations to study conformational changes induced by Ca(2+) and modulated by the N-terminal myristoyl group. Our data on the conformational dynamics of GCAP1 in solution suggest that Ca(2+) stabilizes the protein but induces relatively small changes in the domain structure; however, loss of Ca(+2) mediates a significant global relaxation and movement of N- and C-terminal domains. This model and the previously described "calcium-myristoyl switch" proposed for recoverin indicate significant diversity in conformational changes among these highly homologous NCS proteins with distinct functions.
神经元钙传感器（NCS）是高亲和力的钙结合蛋白，对于调节广泛的生理过程至关重要。鸟苷酸环化酶激活蛋白（GCAPs）是 NCS 家族的成员，负责在低钙浓度下激活视网膜鸟苷酸环化酶（GCs），触发 cGMP 的合成和光感受器细胞恢复到暗适应状态。在这里，我们使用酰胺氢-氘交换和辐射标记以及分子动力学模拟来研究由 Ca（2+）诱导并由 N 端豆蔻酰基调节的构象变化。我们关于 GCAP1 在溶液中的构象动力学的数据表明，Ca（2+）稳定了蛋白质，但对结构域结构的变化相对较小；然而，钙（+2）的丧失介导了 N 端和 C 端结构域的显著全局松弛和运动。该模型和先前为恢复蛋白提出的“钙-豆蔻酰基开关”表明，这些具有不同功能的高度同源 NCS 蛋白之间的构象变化存在显著差异。
