Asmussen Johanne Wirenfeldt, Ambjørn Malene, Bock Elisabeth, Berezin Vladimir
Protein Laboratory, Institute of Neuroscience and Pharmacology, University of Copenhagen, Panum Institute 24.2, Blegdamsvej 3, DK-2200 Copenhagen N, Denmark.
Eur J Cell Biol. 2009 Aug;88(8):433-43. doi: 10.1016/j.ejcb.2009.04.001. Epub 2009 May 14.
Metallothionein (MT) is a metal-binding protein capable of preventing oxidative stress and apoptotic cell death in the central nervous system of mammals, and hence is of putative therapeutic value in the treatment of neurodegenerative disorders. Recently, we demonstrated that a peptide modeled after the beta-domain of MT, EmtinB, induced neurite outgrowth and increased neuronal survival through binding to receptors of the low-density lipoprotein receptor family (LDLR). The present study identified two MT alpha-domain-derived peptide sequences termed EmtinAn and EmtinAc, each consisting of 14 amino acids, as potent stimulators of neuronal differentiation and survival of primary neurons. In addition, we show that a peptide derived from the N-terminus of the MT beta-domain, EmtinBn, promotes neuronal survival. The neuritogenic and survival promoting effects of EmtinAc, similar to MT and EmtinB but not EmtinAn, were dependent on the functional integrity of LDLR. Moreover, EmtinAn and EmtinAc induced activation of extracellular signal-regulated kinase (ERK) and protein kinase B (PKB/Akt). We suggest that multiple functional sites of MT serve to cross-link MT receptor(s), thereby transducing signals leading to an increase in neurite outgrowth and survival.
金属硫蛋白（MT）是一种金属结合蛋白，能够预防哺乳动物中枢神经系统中的氧化应激和凋亡性细胞死亡，因此在神经退行性疾病的治疗中具有潜在的治疗价值。最近，我们证明了一种以MT的β结构域为模型的肽EmtinB，通过与低密度脂蛋白受体家族（LDLR）的受体结合，诱导神经突生长并提高神经元存活率。本研究确定了两个源自MTα结构域的肽序列，分别称为EmtinAn和EmtinAc，每个序列由14个氨基酸组成，它们是原代神经元分化和存活的有效刺激剂。此外，我们表明源自MTβ结构域N端的肽EmtinBn能促进神经元存活。与MT和EmtinB相似但与EmtinAn不同，EmtinAc的促神经突生长和存活作用依赖于LDLR的功能完整性。此外，EmtinAn和EmtinAc诱导细胞外信号调节激酶（ERK）和蛋白激酶B（PKB/Akt）的激活。我们认为MT的多个功能位点用于交联MT受体，从而转导导致神经突生长和存活增加的信号。
