Crystal structure of the extracellular cholinesterase-like domain from neuroligin-2
Crystal structure of the extracellular cholinesterase-like domain from neuroligin-2
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DOI：
10.1073/pnas.0711701105
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发表时间：
2008-02-12
影响因子：
11.1
通讯作者：
Shapiro, Lawrence
中科院分区：
文献类型：
--
作者：
Koehnke, Jesko;Jin, Kiangshu;Shapiro, Lawrence
神经胶质素（NL）是胆碱酯酶样跨膜蛋白家族中无催化活性的成员，可介导神经元突触处的细胞粘附。突触后神经配蛋白通过其细胞外胆碱酯酶结构域与突触前神经毒素（NRXs）参与Ca 2+依赖性的串突触相互作用。这些相互作用可能受到NL胆碱酯酶结构域中两个短剪接插入（称为A和B）的调节。在这里，我们提出的3.3埃晶体结构的胞外域从NL2含有剪接插入A（NL2A）。NL2A的整体结构类似于胆碱酯酶，但几个结构特征是NIL蛋白所独有的。首先，酯酶活性位点区域周围的结构元件在活性酯酶和NL2A之间显著不同。在NL2A分子的相对表面上，A和B剪接插入的位置鉴定NL蛋白的候选NRX相互作用位点。最后，NL同种型的序列比较允许映射在自闭症谱系障碍患者中发现的NL3和NL4中先前鉴定的突变的残基的位置。总体而言，NL2结构有望为解剖NL亚型和突触特异性功能提供有价值的模型。
Neuroligins (NLs) are catalytically inactive members of a family of cholinesterase-like transmembrane proteins that mediate cell adhesion at neuronal synapses. Postsynaptic neuroligins engage in Ca2+-dependent trainssynaptic interactions via their extracellular cholinesterase domain with presynaptic neurexins (NRXs). These interactions may be regulated by two short splice insertions (termed A and B) in the NL cholinesterase domain. Here, we present the 3.3-angstrom crystal structure of the ectodomain from NL2 containing splice insertion A (NL2A). The overall structure of NL2A resembles that of cholinesterases, but several structural features are unique to the NIL proteins. First, structural elements surrounding the esterase active-site region differ significantly between active esterases and NL2A. On the opposite surface of the NL2A molecule, the positions of the A and B splice insertions identify a candidate NRX interaction site of the NL protein. Finally, sequence comparisons of NL isoforms allow for mapping the location of residues of previously identified mutations in NL3 and NL4 found in patients with autism spectrum disorders. Overall, the NL2 structure promises to provide a valuable model for dissecting NL isoform-and synapse-specific functions.