Protein Laboratory, Department of Neuroscience and Pharmacology, Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark.
J Neurochem. 2012 Jun;121(6):915-23. doi: 10.1111/j.1471-4159.2012.07751.x. Epub 2012 Apr 24.
Apart from its hematopoietic activity, erythropoietin (EPO) is also known as a tissue-protective cytokine. In the brain, EPO and its receptor are up-regulated in response to insult and exert pro-survival effects. EPO binds to its receptor (EPOR) via high- and low-affinity binding sites (Sites 1 and 2, respectively), inducing conformational changes in the receptor, followed by the activation of downstream signaling cascades. Based on the crystal structure of the EPO:EPOR(2) complex, we designed a peptide, termed Epobis, whose sequence encompassed amino acids from binding Site 1. The present study shows that the Epobis peptide specifically binds to EPOR and induces neurite outgrowth from primary neurons in an EPOR-expression dependent manner. Furthermore, Epobis promoted the survival of hippocampal and cerebellar neuronal cultures after kainate treatment and KCl deprivation, respectively. Thus, we identified a new functional agonist of EPOR with the potential to promote neuroregeneration and neuroprotection.
除了其造血活性外，促红细胞生成素 (EPO) 也被称为组织保护细胞因子。在大脑中，EPO 和其受体受到损伤的刺激而上调，并发挥抗凋亡作用。EPO 通过高亲和性和低亲和性结合位点（分别为位点 1 和 2）与受体结合，诱导受体构象变化，随后激活下游信号级联反应。基于 EPO:EPOR(2) 复合物的晶体结构，我们设计了一种肽，称为 Epobis，其序列包含结合位点 1 的氨基酸。本研究表明，Epobis 肽特异性结合 EPOR，并以 EPOR 表达依赖性的方式诱导原代神经元的突起生长。此外，Epobis 分别促进了海人酸处理后的海马和小脑神经元培养物的存活以及 KCl 剥夺后的存活。因此，我们鉴定了一种新的 EPOR 功能性激动剂，具有促进神经再生和神经保护的潜力。
