Cryo-EM structure of the Hedgehog release protein Dispatched

The Hedgehog signaling pathway is involved in tissue patterning during embryonic development, as well as the adult tissue homeostasis in multicellular organisms. This pathway in Drosophila melanogaster is initiated by the release of a lipid-modified morphogen, Hedgehog. Secretion of this protein is controlled by a membrane protein Dispatched. Although Dispatched is a critical component of the pathway, the structural basis of its activity has so far not been described. Dispatched is a member of the RND family of transporter proteins, homologous to the Hedgehog receptor Patched. The Korkhov group at the Institute of Biochemistry & Paul Scherrer Institute, in collaboration with the Basler group at the Institute of Molecular Life Sciences, University of Zurich, have described the first structure of the Drosophila melanogaster Dispatched, which was determined by cryo-EM and single particle analysis at 3.2 Å resolution. Dispatched was found to adopt a novel conformation, previously not observed in an RND transporter: the ectodomains of Dispatched were captured in an open conformation suggestive of a possible receptor-chaperone role. A 3D reconstruction of Dispatched bound to the Hedgehog ligand confirmed the ability of Dispatched to bind Hedgehog via the interface formed by the Dispatched ectodomains. The structure may represent the state of Dispatched-Hedgehog complex that precedes the release of the morphogen from the cell surface.

Link to the paper in external page Science Advances.