title: Ligand-induced homotypic and heterotypic clustering of apolipoprotein E receptor 2.
abstract: ApoE Receptor 2 (ApoER2) and the very low density lipoprotein receptor (VLDLR) are type I transmembrane proteins belonging to the LDLR family of receptors. They are neuronal proteins found in synaptic compartments that play an important role in neuronal migration during development. ApoER2 and VLDLR bind to extracellular glycoproteins, such as Reelin and F-spondin, which leads to phosphorylation of adaptor proteins and subsequent activation of downstream signaling pathways. It is thought that ApoER2 and VLDLR undergo clustering upon binding to their ligands, but no direct evidence of clustering has been shown. Here we show strong clustering of ApoER2 induced by the dimeric ligands Fc-RAP, F-spondin, and Reelin but relatively weak clustering with the ligand apoE in the absence of lipoproteins. This clustering involves numerous proteins besides ApoER2, including amyloid precursor protein and the synaptic adaptor protein PSD-95. Interestingly, we did not observe strong clustering of ApoER2 with VLDLR. Clustering was modulated by both extracellular and intracellular domains of ApoER2. Together, our data demonstrate that several multivalent ligands for ApoER2 induce clustering in transfected cells and primary neurons and that these complexes included other synaptic molecules, such as APP and PSD-95.
authors.affiliation: From the Department of Neuroscience, Georgetown University Medical Center, Washington, D. C. 20007 and.
authors.forename: Shailaja D
authors.initials: SD
authors.lastname: Divekar
authors.affiliation: From the Department of Neuroscience, Georgetown University Medical Center, Washington, D. C. 20007 and.
authors.forename: Teal C
authors.initials: TC
authors.lastname: Burrell
authors.affiliation: From the Department of Neuroscience, Georgetown University Medical Center, Washington, D. C. 20007 and.
authors.forename: Jennifer E
authors.initials: JE
authors.lastname: Lee
authors.affiliation: the Department of Molecular Pharmacology and Physiology, University of South Florida College of Medicine, Tampa, Florida 33613.
authors.forename: Edwin J
authors.initials: EJ
authors.lastname: Weeber
authors.affiliation: From the Department of Neuroscience, Georgetown University Medical Center, Washington, D. C. 20007 and gwr2@georgetown.edu.
authors.forename: G William
authors.initials: GW
authors.lastname: Rebeck
mesh_terms: D000818:Animals; D019556:COS Cells; D002465:Cell Movement; D002522:Chlorocebus aethiops; D026502:LDL-Receptor Related Proteins / Q000378:metabolism* / Q000502:physiology; D008024:Ligands; D051379:Mice; D009474:Neurons / Q000502:physiology; D010766:Phosphorylation; D000091042:Reelin Protein
chemical_list: D026502:LDL-Receptor Related Proteins; D008024:Ligands; D000091042:Reelin Protein; C098773:low density lipoprotein receptor-related protein 8; C000717128:Reln protein, mouse
keywords: Alzheimer Disease; Amyloid Precursor Protein (APP); Apolipoprotein E (ApoE); Receptor; Synapse
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