title: Sonic hedgehog protein signals not as a hydrolytic enzyme but as an apparent ligand for patched.
abstract: The amino-terminal signaling domain of the Sonic hedgehog secreted protein (Shh-N), which derives from the Shh precursor through an autoprocessing reaction mediated by the carboxyl-terminal domain, executes multiple functions in embryonic tissue patterning, including induction of ventral and suppression of dorsal cell types in the developing neural tube. An apparent catalytic site within Shh-N is suggested by structural homology to a bacterial carboxypeptidase. We demonstrate here that alteration of residues presumed to be critical for a hydrolytic activity does not cause a loss of inductive activity, thus ruling out catalysis by Shh-N as a requirement for signaling. We favor the alternative, that Shh-N functions primarily as a ligand for the putative receptor Patched (Ptc). This possibility is supported by new evidence for direct binding of Shh-N to Ptc and by a strong correlation between the affinity of Ptc-binding and the signaling potency of Shh-N protein variants carrying alterations of conserved residues in a particular region of the protein surface. These results together suggest that direct Shh-N binding to Ptc is a critical event in transduction of the Shh-N signal.
authors.affiliation: Department of Molecular Biology, Howard Hughes Medical Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
authors.forename: N
authors.initials: N
authors.lastname: Fuse
authors.forename: T
authors.initials: T
authors.lastname: Maiti
authors.forename: B
authors.initials: B
authors.lastname: Wang
authors.forename: J A
authors.initials: JA
authors.lastname: Porter
authors.forename: T M
authors.initials: TM
authors.lastname: Hall
authors.forename: D J
authors.initials: DJ
authors.lastname: Leahy
authors.forename: P A
authors.initials: PA
authors.lastname: Beachy
mesh_terms: D000595:Amino Acid Sequence; D002478:Cells, Cultured; D053823:Hedgehog Proteins; D006493:Heparin / Q000378:metabolism; D006867:Hydrolases / Q000378:metabolism*; D008024:Ligands; D008565:Membrane Proteins / Q000378:metabolism*; D008969:Molecular Sequence Data; D000072079:Patched Receptors; D011506:Proteins / Q000737:chemistry / Q000378:metabolism*; D011956:Receptors, Cell Surface; D015398:Signal Transduction; D013329:Structure-Activity Relationship; D015534:Trans-Activators
chemical_list: D053823:Hedgehog Proteins; D008024:Ligands; D008565:Membrane Proteins; D000072079:Patched Receptors; D011506:Proteins; D011956:Receptors, Cell Surface; D015534:Trans-Activators; D006493:Heparin; D006867:Hydrolases