Cbln1 and Cbln4 Are Structurally Similar but Differ in GluD2 Binding Interactions
Cbln1 and Cbln4 Are Structurally Similar but Differ in GluD2 Binding Interactions
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Cbln1 和 Cbln4 结构相似，但 GluD2 结合相互作用不同
DOI：
10.1016/j.celrep.2017.08.031
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发表时间：
2017
期刊：
影响因子：
8.8
通讯作者：
Ding Jianping
中科院分区：
文献类型：
--
作者：
Zhong Chen;Shen Jinlong;Zhang Huibing;Li Guangyi;Shen Senlin;Wang Fang;Hu Kuan;Cao Longxing;He Yongning;Ding Jianping
与小脑蛋白1（Cbln 1）不同，Cbln 4被报道与受体没有或弱结合，尽管与Cbln 1共享约70%的序列同一性，但Cbln 1在反式突触三联体中桥接神经毒素（Nrxn）受体和δ型谷氨酸受体。在这里，我们报告的晶体结构的同源三聚体的C1 q域的Cbln 1和Cbln 4在2.2和2.3的分辨率，分别。结构的比较表明，Cbln 1和Cbln 4在GluD 2结合上的差异可能是由于它们在CD环中的序列和结构差异。令人惊讶的是，我们发现Cbln 4与Nrxn 1 β结合，并与Nrxn 1 β的层粘连蛋白、nectin、性激素结合球蛋白（LNS）结构域形成稳定的复合物。此外，负染电子显微镜重建六聚体全长Cbln 1在13 nm分辨率和Cbln 4/Nrxn 1 β复合物在19 nm分辨率表明，Nrxn 1 β结合到Cbln 4的N-末端区域，可能通过S4插入片段的β10链。
Unlike cerebellin 1 (Cbln1), which bridges neurexin (Nrxn) receptors and δ-type glutamate receptors in atrans-synaptic triad, Cbln4 was reported to have no or weak binding for the receptors despite sharing ∼70% sequence identity with Cbln1. Here, we report crystal structures of the homotrimers of the C1q domain of Cbln1 and Cbln4 at 2.2 and 2.3 Å resolution, respectively. Comparison of the structures suggests that the difference between Cbln1 and Cbln4 in GluD2 binding might be because of their sequence and structural divergence in loop CD. Surprisingly, we show that Cbln4 binds to Nrxn1β and forms a stable complex with the laminin, nectin, sex-hormone binding globulin (LNS) domain of Nrxn1β. Furthermore, the negative-stain electron microscopy reconstruction of hexameric full-length Cbln1 at 13 Å resolution and that of the Cbln4/Nrxn1β complex at 19 Å resolution suggest that Nrxn1β binds to the N-terminal region of Cbln4, probably through strand β10 of the S4 insert.