Distinct autoregulatory roles of ELFN1 intracellular and extracellular domains on membrane trafficking, synaptic localization, and dimerization.

Autor:	Dunn HA; Department of Neuroscience, The Herbert Wertheim UF Scripps Institute for Biomedical Innovation & Technology, University of Florida, Jupiter, FL 33458, USA; Department of Pharmacology and Therapeutics, University of Manitoba, Winnipeg, MB R3E 0T6, Canada; Division of Neurodegenerative Disorders, St. Boniface Hospital Albrechtsen Research Centre, Winnipeg, Manitoba R2H 2A6, Canada. Electronic address: henry.dunn@umanitoba.ca., Dhaliwal SK; Department of Pharmacology and Therapeutics, University of Manitoba, Winnipeg, MB R3E 0T6, Canada; Division of Neurodegenerative Disorders, St. Boniface Hospital Albrechtsen Research Centre, Winnipeg, Manitoba R2H 2A6, Canada., Chang CT; Department of Neuroscience, The Herbert Wertheim UF Scripps Institute for Biomedical Innovation & Technology, University of Florida, Jupiter, FL 33458, USA., Martemyanov KA; Department of Neuroscience, The Herbert Wertheim UF Scripps Institute for Biomedical Innovation & Technology, University of Florida, Jupiter, FL 33458, USA. Electronic address: kmartemyanov@ufl.edu.
Jazyk:	angličtina
Zdroj:	The Journal of biological chemistry [J Biol Chem] 2024 Dec 13, pp. 108073. Date of Electronic Publication: 2024 Dec 13.
DOI:	10.1016/j.jbc.2024.108073
Abstrakt:	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. Competing Interests: Conflict of interest The authors declare that they have no conflicts of interest with the contents of this article. (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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