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J. Biol. Chem., Vol. 282, Issue 13, 9666-9677, March 30, 2007

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Combined Simulation and Mutagenesis Analyses Reveal the Involvement of Key Residues for Peroxisome Proliferator-activated Receptor Helix 12 Dynamic Behavior^*

Liliane Michalik¹, Vincent Zoete¹, Grigorios Krey^¶, Aurélien Grosdidier^||, Laurent Gelman², Pierre Chodanowski, Jérôme N. Feige, Béatrice Desvergne, Walter Wahli³, and Olivier Michielin^||**4

From the Center for Integrative Genomics and National Research Center "Frontiers in Genetics," University of Lausanne, Le Génopode, CH-1015 Lausanne, Switzerland, the Swiss Institute for Bioinformatics, University of Lausanne, CH-1015 Lausanne, Switzerland, the ^¶National Agricultural Research Foundation, Fisheries Research Institute, Nea Peramos, GR-64007 Kavala, Greece, the ^||Ludwig Institute for Cancer Research and National Research Center "Molecular Oncology," CH-1066 Epalinges, Switzerland, and the ^**Multidisciplinary Oncology Center (CePO), Lausanne University Hospital, CH-1011 Lausanne, Switzerland

The dynamic properties of helix 12 in the ligand binding domain of nuclear receptors are a major determinant of AF-2 domain activity. We investigated the molecular and structural basis of helix 12 mobility, as well as the involvement of individual residues with regard to peroxisome proliferator-activated receptor (PPAR) constitutive and ligand-dependent transcriptional activity. Functional assays of the activity of PPAR helix 12 mutants were combined with free energy molecular dynamics simulations. The agreement between the results from these approaches allows us to make robust claims concerning the mechanisms that govern helix 12 functions. Our data support a model in which PPAR helix 12 transiently adopts a relatively stable active conformation even in the absence of a ligand. This conformation provides the interface for the recruitment of a coactivator and results in constitutive activity. The receptor agonists stabilize this conformation and increase PPAR transcription activation potential. Finally, we disclose important functions of residues in PPAR AF-2, which determine the positioning of helix 12 in the active conformation in the absence of a ligand. Substitution of these residues suppresses PPAR constitutive activity, without changing PPAR ligand-dependent activation potential.

Received for publication, November 13, 2006 , and in revised form, December 22, 2006.

^* This work was supported by the Swiss National Science Foundation and the Etat de Vaud to O. M. (Grants SCORE 3232B0-103172 and 3200B0-103173), B. D., and W. W. Additional grants were received from the Swiss Institute of Bioinformatics, the National Research Centers, Frontiers in Genetics (to W. W.) and Molecular Oncology (to O. M.), and Oncosuisse (Grant OCS01381-08-2003 to O. M.). 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.

¹ Both authors contributed equally to this work.

² Present address: Friedrich Miescher Institut, CH-4058 Basel, Switzerland.

³ To whom correspondence may be addressed. Tel.: 41-21-692-4110; Fax: 41-21-692-4115; E-mail: walter.wahli{at}unil.ch. ⁴ To whom correspondence may be addressed. Tel.: 41-21-692-4053; Fax: 41-21-692-4065; E-mail: olivier.michielin{at}unil.ch.

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