TY - JOUR
T1 - Sonic hedgehog protein signals not as a hydrolytic enzyme but as an apparent ligand for Patched
AU - Fuse, Naoyuki
AU - Maiti, Tapan
AU - Wang, Baolin
AU - Porter, Jeffery A.
AU - Tanaka Hall, Traci M.
AU - Leahy, Daniel J.
AU - Beachy, Philip A.
PY - 1999/9/28
Y1 - 1999/9/28
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=0033613253&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0033613253&partnerID=8YFLogxK
U2 - 10.1073/pnas.96.20.10992
DO - 10.1073/pnas.96.20.10992
M3 - Article
C2 - 10500113
AN - SCOPUS:0033613253
SN - 0027-8424
VL - 96
SP - 10992
EP - 10999
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 20
ER -