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Author Notes:

To whom correspondence should be addressed: E.A. Ortlund, Dept. of Biochemistry, Emory University School of Medicine, Atlanta, GA 30322. Tel.: 404-727-5014; Fax: 404-727-2738; E-mail: eortlun@emory.edu.

We gratefully acknowledge Alexa Mattheyses, Jason Fritz, and Debby Martinson (Integrated Cellular Imaging Core, Emory University) and Shuiliang Yu (Case Western Reserve University) for training in microscopy methods, and Katie Doud (Case Western Reserve University) for generous assistance with the PPARβ/δ activation assays.

Data for 4LKP were collected at Southeast Regional Collaborative Access Team (SER-CAT) 22-BM beamline at the Advanced Photon Source, Argonne National Laboratory.

Use of the Advanced Photon Source was supported by the United States Department of Energy, Office of Science, Office of Basic Energy Sciences, under Contract W-31-109-Eng-38.

Subjects:

Research Funding:

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.

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.

Keywords:

  • Science & Technology
  • Life Sciences & Biomedicine
  • Biochemistry & Molecular Biology
  • RETINOIC ACID
  • NUCLEAR-LOCALIZATION
  • PPAR-BETA/DELTA
  • L-FABP
  • CELL-GROWTH
  • ALPHA
  • GLUCOSE
  • PURIFICATION
  • TRANSPORT
  • FAMILY

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

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Journal Title:

Journal of Biological Chemistry

Volume:

Volume 289, Number 21

Publisher:

, Pages 14941-14954

Type of Work:

Article | Final Publisher PDF

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.

Copyright information:

© 2014 by The American Society for Biochemistry and Molecular Biology, Inc.

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