Sonic hedgehog protein signals not as a hydrolytic enzyme but as an apparent ligand for patched.
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.
Fuse
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Department of Molecular Biology, Howard Hughes Medical Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Maiti
T
T
Wang
B
B
Porter
J A
JA
Hall
T M
TM
Leahy
D J
DJ
Beachy
P A
PA
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
D053823:Hedgehog Proteins; D008024:Ligands; D008565:Membrane Proteins; D000072079:Patched Receptors; D011506:Proteins; D011956:Receptors, Cell Surface; D015534:Trans-Activators; D006493:Heparin; D006867:Hydrolases