Biological processes are dynamically regulated by signaling networks composed of protein kinases and phosphatases. Calcineurin, or PP3, is a conserved phosphoserine/phosphothreonine-specific protein phosphatase and member of the PPP family of phosphatases. Calcineurin is unique, however, in its activation by Ca2+ and calmodulin. This ubiquitously expressed phosphatase controls Ca2+-dependent processes in all human tissues, but is best known for driving the adaptive immune response by dephosphorylating the nuclear factor of the activated T-cells (NFAT) family of transcription factors. Therefore, calcineurin inhibitors, FK506 (tacrolimus), and cyclosporin A serve as immunosuppressants. We describe some of the adverse effects associated with calcineurin inhibitors that result from inhibition of calcineurin in nonimmune tissues, illustrating the many functions of this enzyme that have yet to be elucidated. In fact, calcineurin has essential roles beyond the immune system, from yeast to humans, but since its discovery more than 30 years ago, only a small number of direct calcineurin substrates have been shown (∼75 proteins). This is because of limitations in current methods for identification of phosphatase substrates. Here we discuss recent insights into mechanisms of calcineurin activation and substrate recognition that have been critical in the development of novel approaches for identifying its targets systematically. Rather than comprehensively reviewing known functions of calcineurin, we highlight new approaches to substrate identification for this critical regulator that may reveal molecular mechanisms underlying toxicities caused by calcineurin inhibitor-based immunosuppression.

中文翻译：

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识别旧酶的新底物和功能：钙调神经磷酸酶。


生物过程由蛋白激酶和磷酸酶组成的信号网络动态调节。钙调神经磷酸酶（或 PP3）是一种保守的磷酸丝氨酸/磷酸苏氨酸特异性蛋白磷酸酶，是 PPP 磷酸酶家族的成员。然而，钙调神经磷酸酶的独特之处在于它可以被 Ca2+ 和钙调蛋白激活。这种普遍表达的磷酸酶控制所有人体组织中的 Ca2+ 依赖性过程，但最出名的是通过使活化 T 细胞 (NFAT) 转录因子家族的核因子去磷酸化来驱动适应性免疫反应。因此，钙调神经磷酸酶抑制剂、FK506（他克莫司）和环孢菌素 A 可用作免疫抑制剂。我们描述了与钙调神经磷酸酶抑制剂相关的一些副作用，这些副作用是由于在非免疫组织中抑制钙调神经磷酸酶而产生的，说明了这种酶的许多尚未阐明的功能。事实上，钙调神经磷酸酶在免疫系统之外（从酵母到人类）也发挥着重要作用，但自从 30 多年前发现它以来，只有少数直接的钙调神经磷酸酶底物被证实（约 75 种蛋白质）。这是因为当前鉴定磷酸酶底物的方法存在局限性。在这里，我们讨论了对钙调神经磷酸酶激活和底物识别机制的最新见解，这些机制对于开发系统识别其靶标的新方法至关重要。我们没有全面回顾钙调神经磷酸酶的已知功能，而是重点介绍了这一关键调节因子的底物鉴定新方法，该方法可能揭示基于钙调磷酸酶抑制剂的免疫抑制引起的毒性的分子机制。