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Differential binding of ligands to the apolipoprotein E receptor 2

Item Type:Article
Title:Differential binding of ligands to the apolipoprotein E receptor 2
Creators Name:Andersen, O.M. and Benhayon, D. and Curran, T. and Willnow, T.E.
Abstract:Apolipoprotein E receptor 2 (apoER2) is an important participant in the Reelin signaling pathway that directs cell positioning during embryogenesis. ApoER2 is a cell surface molecule that elicits intracellular signal transduction through binding of Reelin. The structural requirements for Reelin binding to apoER2 and the receptor domains involved in this process are unclear at present. Using a series of receptor mutants, we characterized the interaction of apoER2 with Reelin and compared this interaction to that of apoER2 with the receptor-associated protein (RAP), an apoER2 ligand that does not induce signaling. By surface plasmon resonance we demonstrate that apoER2 exhibits 6-fold higher affinity for Reelin than the very low density lipoprotein receptor (VLDLR), which also functions as a Reelin receptor (KD 0.2 nM versus KD 1.2 nM). Acidic amino acid residues in complement-type repeat domains 1 and 3 of apoER2 are required for Reelin binding. The same regions of the receptor are also bound by RAP with a 25-fold lower affinity (KD 5 nM). Whereas RAP binds to apoER2 with a 1:1 stoichiometry, experimental evidence suggests that Reelin associates with two or more receptor molecules simultaneously to achieve high-affinity interaction. This finding indicates that aggregation of apoER2 by multivalent ligands such as Reelin may be the structural basis for signal transduction.
Keywords:Cultured Cells, Extracellular Matrix Proteins, LDL Receptors, Ligands, Lipoprotein Receptors, Mutation, Nerve Tissue Proteins, Neuronal Cell Adhesion Molecules, Protein Binding, Serine Endopeptidases, Signal Transduction, Site-Directed Mutagenesis, Tyrosine, VLDL Lipoproteins, Animals, Mice
Publisher:American Chemical Society
Page Range:9355-9364
Date:12 August 2003
Official Publication:https://doi.org/10.1021/bi034475p
PubMed:View item in PubMed

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