Ligand Specificity of Brain Lipid-binding Protein

Abstract

Brain lipid-binding protein (BLBP)1 is a brain-specific member of the fatty acid-binding protein (FABP) family that is expressed at high levels in the developing central nervous system (1-3). While the function of BLBP is not clear, several lines of evidence suggest that it plays an important role in neuron/glial interactions during central nervous system development. Thus, the presence of BLBP in both the nucleus and cytoplasm of expressing cells (2) and its dynamic regulation in glial cells in response to neurons (4) both indicate that BLBP may participate in a signaling pathway that is critical for the response of glia to differentiating neurons. Furthermore, the ability of anti-BLBP antibodies to inhibit glial process extension in response to neurons in primary cell cultures prepared during the first postnatal week is consistent with this idea (2). Given these observations, we have been interested in understanding both the regulatory pathways responsible for the dynamic pattern of BLBP expression in the developing central nervous system and its functional role in differentiating glial cells.The high similarity between BLBP and previously characterized FABPs (2) strongly suggests that the function of BLBP in the developing nervous system involves binding to a small hydrophobic ligand, possibly a fatty acid or a fatty acid metabolite. Furthermore, the demonstration that cellular retinoic acid-binding protein (CRABP) transcription is regulated by retinoic acid (5) and the dynamic response of BLBP transcription to neurons in vivo and in vitro (4) suggests that the putative BLBP ligand might also be critical for regulation of BLBP transcription in the developing central nervous system. To understand the role of BLBP, and to investigate the potential mechanisms of its transcriptional control, we have initiated studies aimed at identifying the BLBP ligand. In this study, we present a detailed biochemical characterization of BLBP binding to a variety of potential ligands, as well as a structure/ function analysis of the BLBP binding pockets to identify a physiological ligand for BLBP. We report that the binding specificity of BLBP to common fatty acids is different than that of other FABPs, since it will not bind palmitic acid or arachidinic acid. We suggest that DHA is the physiological ligand for BLBP, since the affinity of this interaction (K d ϳ 10 nM) is the highest yet reported for a FABP/ligand interaction. Finally, we present a structural model for BLBP/DHA interaction that provides insight into both the chemical characterisitics of the ligand that are important for BLBP binding, and some of the key amino acids in the BLBP binding pocket that we demonstrate to be critical for this interaction. These studies provide strong evidence that the role of BLBP in the developing nervous system may be closely related to the essential requirement for DHA in central nervous system development in vivo. EXPERIMENTAL PROCEDURESMaterials-Lipidex 1000 and fatty acids were from Sigma. All radioactive materials (oleic acid, pa...

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