Different residues mediate recognition of 1-O-oleyl-lysophosphatidic acid and rosiglitazone in the ligand binding domain of PPAR1

doi:10.1074/jbc.M510843200

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Papers In Press, published online ahead of print December 1, 2005
J. Biol. Chem, 10.1074/jbc.M510843200
Submitted on October 4, 2005
Revised on November 29, 2005
Accepted on December 1, 2005

Different residues mediate recognition of 1-O-oleyl-lysophosphatidic acid and rosiglitazone in the ligand binding domain of PPAR1

Tamotsu Tsukahara, Ryoko Tsukahara, Satoshi Yasuda, Natalia Makarova, William J. Valentine, Patrick Allison, Hongbin Yuan, Daniel L. Baker, Zaiguo Li, Robert Bittman, Abby Parrill, and Gabor Tigyi

Physiology, University of Tennessee Health Science Center, Memphis, TN 38163

Corresponding Author: gtigyi{at}physio1.utmem.edu

Here we show that a naturally occurring ether analog of lysophosphatidic acid, 1-O-octadecenyl-2-hydroxy-sn-glycero-3-phosphate (AGP), is a high-affinity partial agonist of the peroxisome proliferator-activated receptor 1 (PPAR1). Binding studies using the PPAR ligand binding domain (LBD) showed that [32P]-AGP and [3H]-Rosiglitazone (Rosi) both specifically bind to PPAR and compete with each other. [32P]-AGP bound PPAR-LBD with an affinity (Kd~60 nM) similar to that of Rosi (Kd~40 nM). However, AGP only displaced ~40% of bound [3H]-Rosi even when applied at a 2000-fold excess. Activation of PPAR-dependent reporter gene expression by AGP and Rosi showed similar potency, yet AGP-mediated activation was only 40% that of Rosi at 50 µM. A complex between AGP and PPAR was generated using molecular modeling based on a PPAR crystal structure. AGP interacting residues were compared with Rosi interacting residues identified within the Rosi-PPAR cocrystal. These comparisons showed that the two ligands occupy partially overlapping positions but make different hydrogen bonding and ion-pairing interactions. Site-specific mutants of PPAR-LBD were prepared to examine individual ligand binding. Of these mutants, H323A and H449A showed reduced binding of Rosi but maintained binding of AGP. In contrast, the R288A mutant showed reduced AGP binding but maintained Rosi binding. Fi-nally, alanine replacement of Y473 abolished binding of and activation by Rosi and AGP. These observations indicate that the endogenous lipid mediator AGP is a high-affinity ligand of PPAR but that it binds via interactions distinct from those involved in Rosi binding. These distinct interactions are likely responsible for the partial PPAR agonism of AGP.

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