Structural investigation of Ca2+ signaling and transport across biological membranes

钙离子（Ca2+）是所有生物体内最受严格调控的离子，影响细胞生命的几乎每个方面，因为它们在许多信号转导过程中作为次级信使起着重要作用。在静止细胞中，细胞质Ca2+水平较低。质膜Ca2+- atp酶（PMCAs）通过从细胞质中挤出Ca2+（对抗陡峭的浓度梯度）为信号传导奠定了基础。当细胞被刺激释放Ca2+从细胞内储存（例如通过肌醇1,4,5-三磷酸（IP3）受体（IP3R））和/或当Ca2+通过质膜离子通道进入细胞时，信号传导发生。最近，我们和其他人已经对PMCA和IP3R家族成员的调控域获得了重要的结构见解，然而，关于它们的跨膜域的关键问题仍然存在：这些Ca2+转运体的三维结构是怎样的？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、哺乳动物到原生动物寄生虫等不同物种的PMCAs和IP3受体的结构、功能和调控。进一步（结构）洞察细胞中Ca2+水平的控制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.