Homodimerization and isoform-specific heterodimerization of neuroligins
Homodimerization and isoform-specific heterodimerization of neuroligins
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DOI：
10.1042/bj20120808
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发表时间：
2012-09-01
影响因子：
4.1
通讯作者：
Brose, Nils
中科院分区：
文献类型：
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作者：
Poulopoulos, Alexandros;Soykan, Tolga;Brose, Nils
神经胶质素是中枢神经系统中参与功能性突触建立的突触后粘附蛋白。在啮齿类动物中，四种基因产生在不同突触处起作用的神经配蛋白，具有相应的神经递质和亚型特异性。在本研究中，我们研究了不同的neuroligins之间的相互作用，通过分离内源性低聚复合物使用原位交联的原代神经元。检查海马，纹状体，小脑和脊髓文化，我们发现，神经连接素形成组成型二聚体，包括同聚体，最值得注意的是，神经连接素1/3异聚体。此外，我们发现，神经连接素单体通过涉及神经连接素跨膜结构域的细胞质量控制机制特异性地保留在分泌途径中，确保在细胞表面运输之前发生二聚化。最后，我们确定了自闭症相关的神经连接蛋白突变体的二聚化能力的差异，并发现神经连接蛋白3 R471 C突变体可以与神经连接蛋白1形成异源二聚体。神经连接素二聚化的普遍性质表明，神经连接素功能的单位是二聚体，并提出了有趣的可能性，不同的异源二聚体功能，以及天然和突变体神经连接素之间的相互作用，有助于疾病表型。
Neuroligins are postsynaptic adhesion proteins involved in the establishment of functional synapses in the central nervous system. In rodents, four genes give rise to neuroligins that function at distinct synapses, with corresponding neurotransmitter and subtype specificities. In the present study, we examined the interactions between the different neuroligins by isolating endogenous oligomeric complexes using in situ cross-linking on primary neurons. Examining hippocampal, striatal, cerebellar and spinal cord cultures, we found that neuroligins form constitutive dimers, including homomers and, most notably, neuroligin 1/3 heteromers. Additionally, we found that neuroligin monomers are specifically retained in the secretory pathway through a cellular quality control mechanism that involves the neuroligin transmembrane domain, ensuring that dimerization occurs prior to cell surface trafficking. Lastly, we identified differences in the dimerization capacity of autism-associated neuroligin mutants, and found that neuroligin 3 R471C mutants can form heterodimers with neuroligin 1. The pervasive nature of neuroligin dimerization indicates that the unit of neuroligin function is the dimer, and raises intriguing possibilities of distinct heterodimer functions, and of interactions between native and mutant neuroligins contributing to disease phenotypes.