Synaptic adhesion molecules are essential components of the synapse, yet the diversity of these molecules and their associated functions remain to be fully characterized. Extracellular leucine rich repeat and fibronectin type III domain containing 1 (ELFN1) is a postsynaptic adhesion molecule in the brain that has been increasingly implicated in human neurological disease. ELFN1 is best known for trans-synaptically modulating group III metabotropic glutamate receptors (mGluRs). However, little is known about ELFN1 organization and regulation, which likely govern and precede its ultimate trans-synaptic engagement with group III mGluRs. Herein, we report that the intracellular ELFN1 domain controls membrane trafficking and post-synaptic localization of ELFN1. We pinpoint a ∼30 amino acid juxtamembranous region required for membrane-targeting and discover that ELFN1 exists as an obligate homodimer prior to its trafficking to the membrane. We determine that ELFN1 homodimerization is not appreciably affected by the intracellular region and instead utilizes the extracellular leucine rich repeats (LRR) domain. We find that a single membrane-targeting motif located in one protomer is sufficient for effective trafficking of the ELFN1 homodimer. We further demonstrate that the closest ELFN1 homolog, synaptic adhesion molecule ELFN2, exhibits similar properties and participates in heterodimerization with ELFN1. This establishes distinct autoregulatory roles of ELFN1 intracellular and extracellular domains on membrane trafficking, post-synaptic localization, and dimerization while indicating conservation of the mechanisms across the ELFN subfamily of cell adhesion molecules.

中文翻译：

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ELFN1 细胞内和细胞外结构域对膜运输、突触定位和二聚化的不同自动调节作用。


突触粘附分子是突触的重要组成部分，但这些分子的多样性及其相关功能仍有待充分表征。富含细胞外亮氨酸重复序列和纤连蛋白 III 型结构域包含 1 （ELFN1） 是大脑中的一种突触后粘附分子，与人类神经系统疾病的关系越来越密切。ELFN1 以跨突触调节 III 组代谢型谷氨酸受体 （mGluR） 而闻名。然而，人们对 ELFN1 的组织和调节知之甚少，这可能支配并先于其与 III 组 mGluR 的最终跨突触参与。在此，我们报道细胞内 ELFN1 结构域控制 ELFN1 的膜运输和突触后定位。我们确定了膜靶向所需的 ∼30 个氨基酸的近膜区域，并发现 ELFN1 在运输到膜之前以专性同型二聚体的形式存在。我们确定 ELFN1 同源二聚化不受细胞内区域的明显影响，而是利用细胞外富含亮氨酸重复序列 （LRR） 结构域。我们发现位于一个原聚体中的单个膜靶向基序足以有效运输 ELFN1 同源二聚体。我们进一步证明，最接近的 ELFN1 同源物突触粘附分子 ELFN2 表现出相似的特性并参与与 ELFN1 的异二聚化。这确立了 ELFN1 细胞内和细胞外结构域对膜运输、突触后定位和二聚化的不同自动调节作用，同时表明细胞粘附分子的 ELFN 亚家族的机制是保守的。