Structural investigation of Ca2+ signaling and transport across biological membranes

钙离子（Ca 2+）是所有生物体中调节最严格的离子，几乎影响细胞生命的各个方面，因为它们在许多信号转导过程中作为第二信使发挥重要作用。在静息细胞中，胞质Ca 2+水平低。质膜Ca 2 +-ATP酶（PMCAs）通过从细胞质中挤出Ca 2+（对抗陡峭的浓度梯度）来设置信号传导的阶段。当细胞被刺激从细胞内储存释放Ca 2+时，发生信号传导（例如通过肌醇1，4，5-三磷酸（IP 3）受体（IP 3R））和/或当Ca 2+通过质膜离子通道进入细胞时。最近，我们和其他人已经获得了对PMCA和IP 3R家族成员的调节域的重要结构见解，然而，关键的问题，特别是关于他们的跨膜结构域仍然存在：这些钙离子转运蛋白的三维结构看起来像什么？它们是如何运作的，又是如何监管的？我们的总体目标是研究从植物和哺乳动物到原生动物寄生虫的各种物种的PMCAs和IP 3受体的结构，功能和调节。对细胞中Ca 2+水平控制的进一步（结构）洞察将对从基因表达到信号转导的广泛细胞过程产生巨大影响。

Calcium ions (Ca2+) are the most tightly regulated ions within all organisms and impact nearly every aspect of cellular life as they play an important role as secondary messengers in numerous signal transduction processes. In resting cells the cytoplasmic Ca2+-level is low. Plasmamembrane Ca2+-ATPases (PMCAs) set the stage for signalling by extruding Ca2+ from the cytoplasm (against a steep concentration gradient). Signalling occurs when the cell is stimulated to release Ca2+ from intracellular stores (e.g. via inositol 1,4,5-triphosphate (IP3) receptors (IP3R)) and/or when Ca2+ enters the cell through plasma-membrane ion channels.Recently, we and others have obtained important structural insight into the regulatory domains of PMCA and IP3R family members, however, crucial questions in particular regarding their transmembrane domains remain: How do the three-dimensional structures of these Ca2+- transporters look like? How do they work and how are they regulated? Our overall goal is to investigate structure, function and regulation of PMCAs and IP3 receptors from various species, ranging from plants and mammals to protozoan parasites. Further (structural) insight into the control of Ca2+ levels in cells will have vast implications for a broad range of cellular processes ranging from gene expression to signal transduction.