Elucidating the Molecular Basis of LRP5/6-mediated canonical Wnt signaling

About This Grant

Abstract The canonical Wnt signaling pathway is a master regulator of embryonic development, stem cell renewal, and tissue regeneration. Its dysregulation drives diverse human diseases, including cancer, osteoporosis, and cardiovascular and metabolic disorders. At the center of this pathway are the co-receptors LRP5 and LRP6, which act as dynamic molecular hubs that integrate stimulatory and inhibitory cues. Despite their fundamental roles, how LRP5/6 transition between distinct conformational states and translate ligand binding into precise signaling outcomes remains poorly understood, limiting the development of targeted therapeutic strategies. This proposal aims to decode the structural and mechanistic logic of LRP5/6-mediated Wnt signaling. Leveraging cutting-edge cryo-electron microscopy, biochemistry, and cell-based functional assays, we will define how LRP5/6 dynamically remodel in response to Wnt ligands and antagonists, and how cellular factors such as pH and post-translational modifications fine-tune their activity. By linking receptor structure to function and disease-associated mutations, this work will generate a unifying framework for understanding Wnt pathway regulation and open new avenues for precisely modulating Wnt signaling in tissue regeneration and disease intervention.