Ca2+ coordination controls sonic hedgehog structure and its Scube2-regulated release
Ca2+ coordination controls sonic hedgehog structure and its Scube2-regulated release
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DOI：
10.1242/jcs.205872
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发表时间：
2017-10-01
影响因子：
4
通讯作者：
Grobe, Kay
中科院分区：
文献类型：
--
作者：
Jakobs, Petra;Schulz, Philipp;Grobe, Kay
细胞表面结合配体的蛋白水解加工，称为脱落，是控制细胞间信号传导的基本系统。然而，我们对如何调节脱落的理解仍然不完整。增加双脂化膜相关Sonic hedgehog（Shh）的加工的一种方式是增加底物和脱落酶的密度。这通过从Shh受体结合位点去除脂化的抑制性N-末端肽来释放并激活Shh。Shh的释放和激活由Scube 2 [信号序列，cubulin（CUB）结构域，表皮生长因子（EGF）样蛋白2]增强，这引起了如何实现的问题。在这里，我们表明，Scube 2 EGF结构域负责抑制性Shh N-末端的特异性蛋白水解，并且CUB结构域通过逆转该肽的空间掩蔽来完成该过程。空间掩蔽，反过来，取决于Ca 2+占用的Shh胞外域，揭示了一种新的模式脱落调节在基板水平。重要的是，Scube 2将Shh肽的加工与其脂质介导的质膜定位解偶联，从而解释了长期存在的难题，即N-末端去脂化的Shh在Scube 2表达的脊椎动物中显示出图案化活性，但在缺乏Scube直系同源物的无脊椎动物中不显示图案化活性。
Proteolytic processing of cell-surface-bound ligands, called shedding, is a fundamental system to control cell-cell signaling. Yet, our understanding of how shedding is regulated is still incomplete. One way to increase the processing of dual-lipidated membrane-associated Sonic hedgehog (Shh) is to increase the density of substrate and sheddase. This releases and also activates Shh by the removal of lipidated inhibitory N-terminal peptides from Shh receptor binding sites. Shh release and activation is enhanced by Scube2 [signal sequence, cubulin (CUB) domain, epidermal growth factor (EGF)-like protein 2], raising the question of how this is achieved. Here, we show that Scube2 EGF domains are responsible for specific proteolysis of the inhibitory Shh N-terminus, and that CUB domains complete the process by reversing steric masking of this peptide. Steric masking, in turn, depends on Ca2+ occupancy of Shh ectodomains, unveiling a new mode of shedding regulation at the substrate level. Importantly, Scube2 uncouples processing of Shh peptides from their lipid-mediated juxtamembrane positioning, and thereby explains the long-standing conundrum that N-terminally unlipidated Shh shows patterning activity in Scube2-expressing vertebrates, but not in invertebrates that lack Scube orthologs.