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

Abstract

AbstractSonic 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 domain, can bind two calcium ions. Extracellular matrix (ECM) components in animals include heparan-sulfate proteoglycans, which are analogs of bacterial peptidoglycan and thus potentially involved in the extracellular distribution of Shh. We found that the zinc-coordination fold of Shh is required for its association with ECM as well as for non-cell autonomous signaling. Association with the ECM requires the presence of at least 0.1 μM zinc and is prevented by mutations affecting critical conserved catalytical residues as well as extracellular calcium. Our results demonstrate that the zinc-coordination fold is required for ECM-association and suggest that the putative intrinsic peptidase activity of Shh is required for non-cell autonomous signaling.