Structure and Biophysics, Discovery Sciences, AstraZeneca, Mölndal 431-83, Sweden.
Structure. 2013 Feb 5;21(2):306-13. doi: 10.1016/j.str.2012.12.009. Epub 2013 Jan 17.
The FAM3 superfamily is predicted to contain classical four-helix bundle cytokines, featuring a typical up-up-down-down fold. Two members of FAM3 have been extensively studied. FAM3B PANDER has been shown to regulate glucose homeostasis and β cell function, whereas the homologous FAM3C ILEI has been shown to be involved in epithelial-mesenchymal transition and cancer. Here, we present a three-dimensional structure of a FAM3 protein, murine PANDER. Contrary to previous suggestions, PANDER exhibits a globular β-β-α fold. The structure is composed of two antiparallel β sheets lined by three short helices packing to form a highly conserved water-filled cavity. The fold shares no relation to the predicted four-helix cytokines but is conserved throughout the FAM3 superfamily. The available biological data and the unexpected new fold indicate that FAM3 PANDER and ILEI could represent a new structural class of signaling molecules, with a different mode of action compared to the traditional four-helix bundle cytokines.
FAM3 超家族被预测包含经典的四螺旋束细胞因子，具有典型的上上下下折叠结构。已经对 FAM3 的两个成员进行了广泛研究。FAM3B PANDER 已被证明可调节葡萄糖稳态和β细胞功能，而同源的 FAM3C ILEI 已被证明参与上皮-间充质转化和癌症。在这里，我们展示了一种 FAM3 蛋白，即鼠 PANDER 的三维结构。与之前的建议相反，PANDER 表现出球形 β-β-α 折叠。该结构由两个反平行的β片层组成，由三个短螺旋排列，形成一个高度保守的充满水的空腔。该折叠与预测的四螺旋细胞因子没有关系，但在整个 FAM3 超家族中是保守的。现有的生物学数据和出乎意料的新折叠表明，FAM3 PANDER 和 ILEI 可能代表一种新的信号分子结构类别，与传统的四螺旋束细胞因子相比，具有不同的作用模式。
