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. 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 μM 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. Our results indicate that the putative intrinsic peptidase activity of Shh is required for non-cell autonomous signaling, possibly by enzymatically altering ECM characteristics.

中文翻译：

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Sonic Hedgehog 与细胞外基质的关联需要其锌配位中心

Sonic Hedgehog (Shh) 对锌金属肽酶具有催化裂隙特征，并且与定义 M15A 家族内亚组的一些细菌肽聚糖金属肽酶具有显着的序列相似性，除了具有特征性的锌配位基序外，还可以结合两个钙离子。动物的细胞外基质 (ECM) 成分包括硫酸乙酰肝素蛋白聚糖，它是细菌肽聚糖的类似物，参与 Shh 的细胞外分布。我们发现 Shh 的锌配位中心是其与 ECM 以及非细胞自主信号的关联所必需的。与 ECM 的结合需要存在至少 0.1 μM 的锌，并且通过影响关键保守催化残基的突变来阻止。与保守的钙结合域的存在一致，我们发现细胞外钙抑制了 Shh 的 ECM 关联。我们的结果表明，可能通过酶促改变 ECM 特征，非细胞自主信号传导需要 Shh 的推定内在肽酶活性。