Structural Biology Program, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10021, USA.
Structure. 2013 Sep 3;21(9):1683-9. doi: 10.1016/j.str.2013.07.001. Epub 2013 Jul 25.
The leucine-rich repeat-containing G-protein-coupled receptors (Lgrs) are a large membrane protein family mediating signaling events during development and in the adult organism. Type 2 Lgrs, including Lgr4, Lgr5, and Lgr6, play crucial roles in embryonic development and in several cancers. They also regulate adult stem cell maintenance via direct association with proteins in the Wnt signaling pathways, including Lrp5/6 and frizzled receptors. The R-spondins (Rspo) were recently identified as functional ligands for type 2 Lgrs and were shown to synergize with both canonical and noncanonical Wnt signaling pathways. We determined and report the structure of the Lgr4 ectodomain alone and bound to Rspo1. The structures reveal an extended horseshoe leucine-rich repeat (LRR) receptor architecture that binds, with its concave side, the ligand furin-like repeats via an intimate interface. The molecular details of ligand/receptor recognition provide insight into receptor activation and could serve as template for stem-cell-based regenerative therapeutics development.
富含亮氨酸重复序列的 G 蛋白偶联受体（Lgrs）是一个大型膜蛋白家族，在发育过程和成年生物体中介导信号事件。2 型 Lgrs，包括 Lgr4、Lgr5 和 Lgr6，在胚胎发育和几种癌症中发挥关键作用。它们还通过与 Wnt 信号通路中的蛋白质（包括 Lrp5/6 和 frizzled 受体）直接结合，调节成年干细胞的维持。R 螺旋蛋白（Rspo）最近被确定为 2 型 Lgr 的功能配体，并显示与经典和非经典 Wnt 信号通路协同作用。我们确定并报告了 Lgr4 外显子结构域与其结合 Rspo1 的结构。这些结构揭示了一种扩展的马蹄形富含亮氨酸重复序列（LRR）受体结构，通过紧密的界面，其凹面与配体的弗林样重复结合。配体/受体识别的分子细节提供了对受体激活的深入了解，并可作为基于干细胞的再生治疗开发的模板。
