title: Cooperative folding and ligand-binding properties of LRP6 beta-propeller domains.
abstract: Wnt/beta-catenin signaling controls cell growth during development, and its misregulation in adults can cause human diseases. LRP6, the essential co-receptor for the Wnt pathway, consists of four beta-propeller domains flanked by epidermal growth factor repeats in its extracellular region. To understand the maturation and ligand-binding properties of individual BP domains, we generated soluble receptor consisting of individual BPs, as well as combinations of these domains. We show that BP1, BP2, and BP4 each can be folded and secreted, and their secretion was enhanced by co-expression of Mesd, a molecular chaperone essential for LRP6 folding and maturation. BP3 is not secreted when expressed on its own or in combination with BP2 or BP1 and 2 (BP12); however, folding and secretion of BP3 is vastly enhanced when expressed together with BP4. Similar cooperative folding and maturation was observed between BP1 and BP2. These results suggest that BP1 forms a functional folding unit with BP2, whereas BP3 folds together with BP4. Using these BP constructs, we also found that BP12 and BP34 constitute independent ligand-binding domains capable of binding Wnt3a, Dkk1, and Mesd. The ability of Mesd to block the binding of both Wnt3a and Dkk1 to LRP6 enables this specialized chaperone to function as a Wnt signaling modulator. Together, our studies reveal unique properties of the LRP6 BP domains and provide novel tools to understand LRP6 function in ligand binding and Wnt signaling. Our results also support the development of soluble LRP6 receptors and Mesd as potential therapeutic molecules that target Wnt signaling.
authors.affiliation: Department of Pediatrics, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
authors.forename: Chia-Chen
authors.initials: CC
authors.lastname: Liu
authors.forename: Chelsea
authors.initials: C
authors.lastname: Pearson
authors.forename: Guojun
authors.initials: G
authors.lastname: Bu