Sonic hedgehog protein signals not as a hydrolytic enzyme but as an apparent ligand for Patched
Sonic hedgehog protein signals not as a hydrolytic enzyme but as an apparent ligand for Patched
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DOI：
10.1073/pnas.96.20.10992
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发表时间：
1999-09-28
影响因子：
11.1
通讯作者：
Beachy, PA
中科院分区：
文献类型：
--
作者：
Fuse, N;Maiti, T;Beachy, PA
Sonic hedgehog分泌蛋白（Shh-N）的氨基末端信号结构域通过羧基末端结构域介导的自加工反应衍生自Shh前体，在胚胎组织图案形成中执行多种功能，包括在发育中的神经管中诱导腹侧细胞类型和抑制背侧细胞类型。Shh-N内的一个明显的催化位点的结构同源性细菌羧肽酶，我们在这里证明，改变残基假定是关键的水解活性不会导致诱导活性的损失，从而排除催化Shh-N作为一个信号的要求。我们倾向于另一种选择，即Shh-N主要作为推定受体Patched（Ptc）的配体发挥作用，这种可能性得到了Shh-N与Ptc直接结合的新证据以及Ptc结合亲和力与Shh-N蛋白变体的信号传导效力之间的强相关性的支持，所述Shh-N蛋白变体在蛋白表面的特定区域中携带保守残基的改变。这些结果共同表明，直接Shh-N结合Ptc是一个关键的事件在Shh-N信号转导。
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.