Protein Laboratory, Department of Neuroscience and Pharmacology, Panum Institute, University of Copenhagen, Blegdamsvej 3C, Bldg. 24.2, 2200 Copenhagen, Denmark.
FASEB J. 2010 Apr;24(4):1139-50. doi: 10.1096/fj.09-140509. Epub 2009 Dec 1.
Neuroplastin (Np) is a glycoprotein belonging to the immunoglobulin superfamily of cell adhesion molecules (CAMs) and existing in two isoforms, Np55 and Np65, named according to their molecular weights. The extracellular part of Np65 contains three immunoglobulin (Ig)-like modules (Ig1, Ig2, and Ig3), whereas Np55 lacks the Ig1 module. Of these two isoforms, only Np65 is involved in homophilic interactions resulting in cell adhesion, whereas the role of Np55 is poorly understood. The present study reports for the first time the crystal structure of the ectodomain of Np55 at 1.95-A resolution and demonstrates that Np55 binds to and activates the fibroblast growth factor receptor 1 (FGFR1). Furthermore, we identify a sequence motif in the Ig2 module of Np55 interacting with FGFR1 and show that a synthetic peptide encompassing this motif, termed narpin, binds to and activates FGFR1. We show that both Np55 and the narpin peptide induce neurite outgrowth through FGFR1 activation and that Np55 increases synaptic calcium concentration in an FGFR1-dependent manner. Moreover, we demonstrate that narpin has an antidepressive-like effect in rats subjected to the forced swim test, suggesting that Np55-induced signaling may be involved in synaptic plasticity in vivo. Owczarek, S., Kiryushko, D., Larsen, M. H., Kastrup, J. S., Gajhede, M., Sandi, C., Berezin, V., Bock, E., Soroka, V. Neuroplastin-55 binds to and signals through the fibroblast growth factor receptor.
神经粘连蛋白（Np）是一种糖蛋白，属于细胞黏附分子（CAMs）的免疫球蛋白超家族，存在两种同工型，Np55 和 Np65，根据其分子量命名。Np65 的细胞外部分包含三个免疫球蛋白（Ig）样模块（Ig1、Ig2 和 Ig3），而 Np55 缺乏 Ig1 模块。在这两种同工型中，只有 Np65 参与同源相互作用导致细胞黏附，而 Np55 的作用知之甚少。本研究首次报道了 Np55 胞外结构域的晶体结构，分辨率为 1.95A，并证实 Np55 与成纤维细胞生长因子受体 1（FGFR1）结合并激活其活性。此外，我们鉴定了 Np55 的 Ig2 模块中的一个与 FGFR1 相互作用的序列基序，并表明包含该基序的合成肽，称为 narpin，与 FGFR1 结合并激活其活性。我们表明，Np55 和 narpin 肽均通过 FGFR1 激活诱导神经突生长，并且 Np55 以 FGFR1 依赖的方式增加突触钙浓度。此外，我们证明 narpin 在经受强迫游泳试验的大鼠中具有抗抑郁样作用，表明 Np55 诱导的信号可能参与体内突触可塑性。Owczarek, S., Kiryushko, D., Larsen, M. H., Kastrup, J. S., Gajhede, M., Sandi, C., Berezin, V., Bock, E., Soroka, V. Neuroplastin-55 与成纤维细胞生长因子受体结合并发出信号。
