The co-receptor Tetraspanin12 directly captures Norrin to promote ligand-specific β-catenin signaling

• DOI: 10.7554/elife.96743
• Publication Date: 2024-04-22T11:25:08Z
• Authors: Elise S Bruguera; Jacob P Mahoney; William I Weis
• Keywords: Wnt; co-receptor; QH301-705.5; Science; nanodiscs; Q; R; cell signaling; specificity; Medicine; Biology (General); Article; Developmental Biology

Wnt/β-catenin signaling directs animal development and tissue renewal in a tightly controlled, cell- tissue-specific manner. In the mammalian central nervous system, atypical ligand Norrin controls angiogenesis maintenance of blood-brain barrier blood-retina through pathway. Like Wnt, activates by binding heterodimerizing receptors Frizzled (Fzd) low-density lipoprotein receptor-related protein 5 or 6 (LRP5/6), leading to membrane recruitment intracellular transducer Dishevelled (Dvl) ultimately stabilizing transcriptional coactivator β-catenin. Unlike cystine knot only signals Fzd4 additionally requires co-receptor Tetraspanin12 (Tspan12); however, mechanism underlying Tspan12-mediated signal enhancement is unclear. It has been proposed that Tspan12 integrates into Norrin-Fzd4 complex enhance affinity otherwise allosterically modulate signaling. Here, we measure direct, high-affinity between purified lipid environment use AlphaFold models interrogate this interaction interface. We find can simultaneously bind pre-formed Tspan12/Fzd4 heterodimer, as well cells co-expressing Fzd4, more efficiently capture low concentrations than alone. also show competes with both heparan sulfate proteoglycans LRP6 for does not impact Fzd4-Dvl presence absence Norrin. Our findings suggest Dvl, but instead functions directly upstream