America Michelle, Bostaille Naguissa, Eubelen Marie, Martin Maud, Stainier Didier Y R, Vanhollebeke Benoit
Laboratory of Neurovascular Signaling, Department of Molecular Biology, ULB Neuroscience Institute, Université libre de Bruxelles (ULB), Gosselies 6041, Belgium.
Department of Developmental Genetics, Max Planck Institute for Heart and Lung Research, 61231 Bad Nauheim, Germany.
Cell Rep. 2022 May 31;39(9):110902. doi: 10.1016/j.celrep.2022.110902.
Within the central nervous system, Wnt7a/b are unambiguously discriminated from other Wnt ligands by an endothelial receptor complex made of the glycosylphosphatidylinositol (GPI)-anchored Reck and the adhesion G protein-coupled receptor (GPCR) Gpr124. Reck is a Wnt7a/b-specific receptor, while Gpr124 facilitates the delivery of Reck-bound Wnt7a/b ligands to Frizzled, through partially characterized mechanisms. We report that, in zebrafish, the Gpr124-Frizzled interactions are dominated by intracellular scaffolds that exploit the striking molecular mimicry between Gpr124 and Frizzled intracellular domains (ICDs): an internal Dvl-binding motif and a C-terminal ETTV motif that recruits Dlg4 and Magi3. By contrast, mammalian Gpr124 receptors exhibit an ICD-independent interaction mechanism governed by species-specific attributes of their transmembrane and extracellular domains. This mechanism seemingly evolved to replace the Dvl-mediated mechanism. By contrasting zebrafish, mouse, and human Gpr124, this study provides insights into the evolution of Gpr124/Reck function across the vertebrate clade, a receptor complex uniquely implicated in Wnt ligand-specific cellular responses.
在中枢神经系统中，糖基磷脂酰肌醇（GPI）锚定的Reck和粘附G蛋白偶联受体（GPCR）Gpr124组成的内皮受体复合物能够明确区分Wnt7a/b与其他Wnt配体。Reck是Wnt7a/b特异性受体，而Gpr124通过部分已明确的机制促进与Reck结合的Wnt7a/b配体传递至卷曲蛋白（Frizzled）。我们报道，在斑马鱼中，Gpr124与Frizzled的相互作用主要由细胞内支架介导，这些支架利用了Gpr124与Frizzled细胞内结构域（ICD）之间显著的分子模拟：一个内部的Dvl结合基序和一个招募Dlg4和Magi3的C末端ETTV基序。相比之下，哺乳动物的Gpr124受体表现出一种不依赖ICD的相互作用机制，该机制由其跨膜和细胞外结构域的物种特异性属性所决定。这种机制似乎是为了取代由Dvl介导的机制而进化而来。通过对比斑马鱼、小鼠和人类的Gpr124，本研究深入探讨了脊椎动物进化枝中Gpr124/Reck功能的演变，这是一种独特地参与Wnt配体特异性细胞反应的受体复合物。
