Association of Sonic Hedgehog with the extracellular matrix requires its zinc-coordination center

Background Sonic Hedgehog (Shh) has a catalytic cleft characteristic for zinc metallopeptidases and has significant sequence similarities with some bacterial peptidoglycan metallopeptidases defining a subgroup within the M15A family that, besides having the characteristic zinc coordination motif, can bind two calcium ions. Extracellular matrix (ECM) components in animals include heparan-sulfate proteoglycans, which are analogs of bacterial peptidoglycan and are involved in the extracellular distribution of Shh. Results We found that the zinc-coordination center of Shh is required for its association to the ECM as well as for non-cell autonomous signaling. Association with the ECM requires the presence of at least 0.1 mu M zinc and is prevented by mutations affecting critical conserved catalytical residues. Consistent with the presence of a conserved calcium binding domain, we find that extracellular calcium inhibits ECM association of Shh. Conclusions Our results indicate that the putative intrinsic peptidase activity of Shh is required for non-cell autonomous signaling, possibly by enzymatically altering ECM characteristics.

Automated summary

Our research indicates that the intrinsic peptidase activity of Sonic Hedgehog is essential for non-cell autonomous signaling, possibly by enzymatically altering extracellular matrix characteristics. The zinc-coordination center of Shh is crucial for its association with the extracellular matrix, requiring at least 0.1 mu M zinc, and this association is inhibited by extracellular calcium.