Structural Basis for Ligand Regulation of the Fatty Acid-binding Protein 5, Peroxisome Proliferator-activated Receptor beta/delta (FABP5-PPAR beta/delta) Signaling Pathway

• Type of Material: Article
• Authors: Eric H. Armstrong, Emory University; Devrishi Goswami, The Scripps Research Institute; Patrick R. Griffin, The Scripps Research Institute; Noa Noy, Case Western Reserve University; Eric Ortlund, Emory University
• Language: English
• Date: 2014-05-23
• Publisher: American Society for Biochemistry and Molecular Biology
• Publication Version: Final Published Version
• Copyright Statement: © 2014 by The American Society for Biochemistry and Molecular Biology, Inc.
• Final Published Version (URL): http://dx.doi.org/10.1074/jbc.M113.514646
• Title of Journal or Parent Work: Journal of Biological Chemistry
• ISSN: 0021-9258
• Volume: 289
• Issue: 21
• Start Page: 14941
• End Page: 14954
• Grant/Funding Information: This work was also supported by start-up funds from Emory University (to E. A. O.).; E.H.A. was supported by National Institute of Health Graduate Training Grant 5T32GM008602 from Pharmacological Sciences, Emory University.; This work was supported, in whole or in part, by National Institutes of Health Grant R01 DK060684 and Grant P30CA138292 from the Emory University Integrated Cellular Imaging Microscopy Core of the Winship Cancer Institute comprehensive cancer center.
• Keywords: RETINOIC ACID; PPAR-BETA/DELTA; PURIFICATION; ALPHA; FAMILY; L-FABP; GLUCOSE; Life Sciences & Biomedicine; Biochemistry & Molecular Biology; Science & Technology; TRANSPORT; NUCLEAR-LOCALIZATION; CELL-GROWTH
• Research Categories: Biology, Molecular; Biology, Physiology; Chemistry, Biochemistry

Abstract

Fatty acid-binding proteins (FABPs) are a widely expressed group of calycins that play a well established role in solubilizing cellular fatty acids. Recent studies, however, have recast FABPs as active participants in vital lipid-signaling pathways. FABP5, like its family members, displays a promiscuous ligand binding profile, capable of interacting with numerous long chain fatty acids of varying degrees of saturation. Certain "activating" fatty acids induce the protein's cytoplasmic to nuclear translocation, stimulating PPARβ/δ transactivation; however, the rules that govern this process remain unknown. Using a range of structural and biochemical techniques, we show that both linoleic and arachidonic acid elicit FABP5's translocation by permitting allosteric communication between the ligand-sensing β2 loop and a tertiary nuclear localization signal within the α-helical cap of the protein. Furthermore, we show that more saturated, nonactivating fatty acids inhibit nuclear localization signal formation by destabilizing this activation loop, thus implicating FABP5 specifically in cis-bonded, polyunsaturated fatty acid signaling.