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J Biol Chem. 2014 May 23;289(21):14941-54. doi: 10.1074/jbc.M113.514646. Epub 2014 Apr 1.

Structural basis for ligand regulation of the fatty acid-binding protein 5, peroxisome proliferator-activated receptor β/δ (FABP5-PPARβ/δ) signaling pathway.

Author information

1
From the Department of Biochemistry, Discovery and Developmental Therapeutics, Winship Cancer Institute, Emory University School of Medicine, Atlanta, Georgia 30322.
2
the Department of Molecular Therapeutics, The Scripps Research Institute, Jupiter, Florida 33458, and.
3
the Departments of Pharmacology and Nutrition, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106.
4
From the Department of Biochemistry, Discovery and Developmental Therapeutics, Winship Cancer Institute, Emory University School of Medicine, Atlanta, Georgia 30322, eortlun@emory.edu.

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.

KEYWORDS:

Fatty Acid; Fatty Acid-binding Protein; Lipids; Nuclear Receptors; Polyunsaturated Fatty Acids; Structural Biology

PMID:
24692551
PMCID:
PMC4031543
DOI:
10.1074/jbc.M113.514646
[Indexed for MEDLINE]
Free PMC Article

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