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J. Biol. Chem., Vol. 280, Issue 28, 26543-26556, July 15, 2005

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Structural Determinants of the Agonist-independent Association of Human Peroxisome Proliferator-activated Receptors with Coactivators^*

Ferdinand Molnár, Merja Matilainen, and Carsten Carlberg

From the Department of Biochemistry, University of Kuopio, Kuopio FIN-70211, Finland

Lipid homeostasis is controlled by various nuclear receptors (NRs), including the peroxisome proliferator-activated receptors (PPAR, , and ), which sense lipid levels and regulate their metabolism. Here we demonstrate that human PPARs have a high basal activity and show ligand-independent coactivator (CoA) association comparable with the NR constitutive androstane receptor. Using PPAR as an example, we found that four different amino acid groups contribute to the ligand-independent stabilization of helix 12 of the PPAR ligand-binding domain. These are: (i) Lys³²⁹ and Glu⁴⁹⁹, mediating a charge clamp-type stabilization of helix 12 via a CoA bridge; (ii) Glu³⁵², Arg⁴²⁵, and Tyr⁵⁰⁵, directly stabilizing the helix via salt bridges and hydrogen bonds; (iii) Lys³⁴⁷ and Asp⁵⁰³, interacting with each other as well as contacting the CoA; and (iv) His³⁵¹, Tyr³⁵⁵, His⁴⁷⁷, and Tyr⁵⁰¹, forming a hydrogen bond network. These amino acids are highly conserved within the PPAR subfamily, suggesting that the same mechanism may apply for all three PPARs. Phylogenetic trees of helix 12 amino acid and nucleotide sequences of all crystallized NRs and all human NRs, respectively, indicated a close relationship of PPARs with constitutive androstane receptor and other constitutive active members of the NR superfamily. Taking together, the ligand-independent tight control of the position of the PPAR helix 12 provides an effective alternative for establishing an interaction with CoA proteins. This leads to high basal activity of PPARs and provides an additional view on PPAR signaling.

Received for publication, March 4, 2005 , and in revised form, April 29, 2005.

^* This work was supported by the Academy of Finland, the Juselius Foundation, and the Finnish Technology Agency TEKES. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence should be addressed: Dept. of Biochemistry, University of Kuopio, P. O. Box 1627, Kuopio FIN-70211, Finland. Tel.: 358-17-163-062; Fax: 358-17-281-1510; E-mail: carlberg{at}messi.uku.fi.

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