Open AccessSonic hedgehog protein signals not as a hydrolytic enzyme but as an apparent ligand for Patched
Author(s) -
Naoyuki Fuse,
Tapan Maiti,
Baolin Wang,
Jeffery A. Porter,
Traci M. Tanaka Hall,
Daniel J. Leahy,
Philip A. Beachy
Publication year - 1999
Publication title -
proceedings of the national academy of sciences of the united states of america
Language(s) - English
Resource type - Journals
eISSN - 1091-6490
pISSN - 0027-8424
DOI - 10.1073/pnas.96.20.10992
Subject(s) - sonic hedgehog , patched , signal transduction , hedgehog signaling pathway , microbiology and biotechnology , biochemistry , biology , ligand (biochemistry) , chemistry , enzyme , hedgehog , smoothened , receptor
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.