Synaptic adhesion proteins play a critical role in the formation and maintenance of synapses in the developing nervous system. Errors in synaptic adhesion constitute the molecular basis of many neuropsychiatric disorders, including schizophrenia, bipolar disorder, Tourette syndrome, and autism. Slit- and Trk-like proteins (Slitrks) are a family of leucine-rich repeat containing transmembrane proteins that promote synaptogenesis. These proteins localize to the postsynaptic density, where they induce synapse formation via trans-synaptic interactions with receptor protein tyrosine phosphatases. While trans-synaptic binding partners of Slitrks have been reported, little is known about the intracellular proteins that associate with Slitrks. Here we report an interaction between Slitrk2 and members of the PSD-95 subfamily of membrane associated guanylate kinases (MAGUKs). Coimmunoprecipitation from postnatal mouse brain indicates that PSD-93 and PSD-95 associate with Slitrk2 in vivo. Mapping analysis in yeast demonstrates that Slitrk2 interacts directly with PSD-95 via a non-canonical Src homology 3 (SH3) domain binding motif that associates with the SH3 domain of PSD-95. We also show that PSD-95 induces robust clustering of Slitrk2 in 293T cells, and deletion of the SH3 domain in PSD-95 or the SH3 domain binding motif in Slitrk2 reduces this clustering. These data confirm PSD-95 as the first known intracellular binding partner of Slitrk2. Future studies will examine if Slitrk-MAGUK interactions mediate localization of Slitrks to synaptic sites and facilitate recruitment of additional intracellular signaling molecules involved in postsynaptic differentiation.

中文翻译：

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MAGUK支架蛋白作为突触粘附蛋白Slitrk2的细胞内结合伴侣的鉴定。

突触粘附蛋白在发育中的神经系统中突触的形成和维持中起关键作用。突触粘附的错误构成许多神经精神疾病的分子基础，包括精神分裂症，双相情感障碍，图雷特综合症和自闭症。Slit-和Trk-like蛋白（Slitrks）是富含亮氨酸的重复序列家族，含有促进突触形成的跨膜蛋白。这些蛋白质定位于突触后密度，在那里它们通过与受体蛋白酪氨酸磷酸酶的反式突触相互作用诱导突触形成。虽然已经报道了Slitrks的反突触结合伴侣，但对与Slitrks缔合的细胞内蛋白知之甚少。在这里，我们报告Slitrk2和膜相关鸟苷酸激酶（MAGUKs）的PSD-95亚家族成员之间的相互作用。产后小鼠大脑的免疫共沉淀表明PSD-93和PSD-95在体内与Slitrk2相关。酵母中的作图分析表明，Slitrk2通过与PSD-95的SH3结构域相关的非规范Src同源性3（SH3）域结合基序与PSD-95直接相互作用。我们还显示，PSD-95在293T细胞中诱导了Slitrk2的强大聚类，而PSD-95中的SH3域的缺失或Slitrk2中的SH3域结合基序的缺失减少了这种聚类。这些数据证实PSD-95是Slitrk2的第一个已知的细胞内结合伴侣。