LRRTMs and neuroligins bind neurexins with a differential code to cooperate in glutamate synapse development.
LRRTMs and neuroligins bind neurexins with a differential code to cooperate in glutamate synapse development.
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DOI：
10.1523/jneurosci.0470-10.2010
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发表时间：
2010-06-02
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影响因子：
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通讯作者：
Craig AM
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文献类型：
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作者：
Siddiqui TJ;Pancaroglu R;Kang Y;Rooyakkers A;Craig AM
富含亮氨酸重复跨膜神经元蛋白（LRRTMs）最近被发现指导突触前和介导突触后神经元的分化。在候选筛选中，我们鉴定出在剪接位点4（−S4）缺少插入片段的neurexin 1β作为LRRTM 2的配体。神经毒素以类似的亲和力结合LRRTM 2，但与结合神经配蛋白-1的密码不同（神经配蛋白-1在谷氨酸突触的主要形式，含有B剪接位点插入物）。尽管神经连接蛋白-1结合neurexin 1、2和3 β但不结合α变体，而不管剪接位点4处的插入，LRRTM 2结合neurexin 1、2和3 α和β变体，特异性地缺乏剪接位点4处的插入。我们进一步表明，这种结合代码是保守的LRRTM 1，家庭成员与精神分裂症和利手，和代码是功能的共培养半突触形成试验。突变LRRTM 2以防止与神经毒素结合，从而消除LRRTMs的突触前诱导活性。值得注意的是，neurexins的突变显示neurexin 1 β（−S4）上的结合面与结构上不同的LRRTM 2和neuroligin-1配偶体高度重叠。最后，我们在这里探索神经连接素-1和LRRTM 2在突触调节中的相互作用。在神经元培养物中，LRRTM 2在促进突触分化方面比neuroligin-1更有效，并且最重要的是，这两个neurexin结合伴侣家族以相加或协同的方式合作。因此，我们提出了一个突触密码假说，表明neurexins的LRRTM和神经配素的合作活动的主调节器。
Leucine rich repeat transmembrane neuronal proteins (LRRTMs) were recently found to instruct presynaptic and mediate postsynaptic glutamatergic differentiation. In a candidate screen, here we identify neurexin 1β lacking an insert at splice site 4 (−S4) as a ligand for LRRTM2. Neurexins bind LRRTM2 with a similar affinity but distinct code from the code for binding neuroligin-1 (the predominant form of neuroligin-1 at glutamate synapses, containing the B splice site insert). Whereas neuroligin-1 binds to neurexin 1, 2 and 3 β but not α variants regardless of insert at splice site 4, LRRTM2 binds to neurexin 1, 2 and 3 α and β variants specifically lacking an insert at splice site 4. We further show that this binding code is conserved in LRRTM1, the family member linked to schizophrenia and handedness, and that the code is functional in a co-culture hemi-synapse formation assay. Mutagenesis of LRRTM2 to prevent binding to neurexins abolishes presynaptic inducing activity of LRRTMs. Remarkably, mutagenesis of neurexins shows that the binding face on neurexin1β(−S4) is highly overlapping for the structurally distinct LRRTM2 and neuroligin-1 partners. Finally, we explore here the interplay of neuroligin-1 and LRRTM2 in synapse regulation. In neuron cultures, LRRTM2 is more potent than neuroligin-1 in promoting synaptic differentiation, and, most importantly, these two families of neurexin-binding partners cooperate in an additive or synergistic manner. Thus we propose a synaptic code hypothesis suggesting that neurexins are master regulators of the cooperative activities of LRRTMs and neuroligins.