Dunn Henry A, Dhaliwal Simran K, Chang Chu-Ting, Martemyanov Kirill A
Department of Neuroscience, The Herbert Wertheim UF Scripps Institute for Biomedical Innovation & Technology, University of Florida, Jupiter, Florida, USA; Department of Pharmacology and Therapeutics, University of Manitoba, Winnipeg, Canada; Division of Neurodegenerative Disorders, St Boniface Hospital Albrechtsen Research Centre, Winnipeg, Manitoba, Canada.
Department of Pharmacology and Therapeutics, University of Manitoba, Winnipeg, Canada; Division of Neurodegenerative Disorders, St Boniface Hospital Albrechtsen Research Centre, Winnipeg, Manitoba, Canada.
J Biol Chem. 2025 Jan;301(1):108073. doi: 10.1016/j.jbc.2024.108073. Epub 2024 Dec 13.
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.
突触粘附分子是突触的重要组成部分，然而这些分子的多样性及其相关功能仍有待充分表征。富含亮氨酸重复序列和III型纤连蛋白结构域的细胞外蛋白1（ELFN1）是大脑中的一种突触后粘附分子，越来越多地与人类神经疾病相关。ELFN1最出名的是其对III组代谢型谷氨酸受体（mGluRs）的跨突触调节作用。然而，对于ELFN1的组织和调控知之甚少，而这可能决定并先于其最终与III组mGluRs的跨突触相互作用。在此，我们报告细胞内ELFN1结构域控制ELFN1的膜运输和突触后定位。我们确定了一个约30个氨基酸的近膜区域，它是膜靶向所必需的，并发现ELFN1在运输到膜之前以一种必需的同二聚体形式存在。我们确定ELFN1的同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。我们发现位于一个亚基中的单个膜靶向基序足以实现ELFN1同二聚体的有效运输。我们进一步证明，最接近的ELFN1同源物，即突触粘附分子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在膜运输、突触后定位和二聚化方面独特的自调节作用，同时表明细胞粘附分子ELFN亚家族中机制的保守性。
