Structural Basis for Ligand Regulation of the Fatty Acid-Binding Protein 5, Peroxisome Proliferator-Activated Receptor β/δ (FABP5-PPARβ/δ) Signaling Pathway

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

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Arachidonic Acid / chemistry
  • Arachidonic Acid / metabolism
  • Arachidonic Acid / pharmacology
  • Binding Sites
  • COS Cells
  • Cell Nucleus / drug effects
  • Cell Nucleus / metabolism
  • Chlorocebus aethiops
  • Cytoplasm / drug effects
  • Cytoplasm / metabolism
  • Fatty Acid-Binding Proteins / chemistry
  • Fatty Acid-Binding Proteins / genetics
  • Fatty Acid-Binding Proteins / metabolism*
  • Fatty Acids / chemistry
  • Fatty Acids / metabolism*
  • Fatty Acids / pharmacology
  • Humans
  • Ligands
  • Linoleic Acid / chemistry
  • Linoleic Acid / metabolism
  • Linoleic Acid / pharmacology
  • MCF-7 Cells
  • Models, Molecular
  • Molecular Structure
  • Mutation
  • Nuclear Localization Signals / chemistry
  • Nuclear Localization Signals / metabolism
  • PPAR gamma / genetics
  • PPAR gamma / metabolism*
  • PPAR-beta / genetics
  • PPAR-beta / metabolism*
  • Protein Binding
  • Protein Structure, Secondary
  • Protein Structure, Tertiary
  • Protein Transport / drug effects
  • Transcriptional Activation / drug effects

Substances

  • FABP5 protein, human
  • Fatty Acid-Binding Proteins
  • Fatty Acids
  • Ligands
  • Nuclear Localization Signals
  • PPAR gamma
  • PPAR-beta
  • Arachidonic Acid
  • Linoleic Acid