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J. Biol. Chem., Vol. 283, Issue 29, 20220-20230, July 18, 2008

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Communication between the ERR Homodimer Interface and the PGC-1 Binding Surface via the Helix 8–9 Loop^*

Holger Greschik, Magnus Althage^¶, Ralf Flaig¹, Yoshiteru Sato, Virginie Chavant, Carole Peluso-Iltis, Laurence Choulier^||, Philippe Cronet^¶2, Natacha Rochel, Roland Schüle, Per-Erik Strömstedt^¶, and Dino Moras³

From the Département de Biologie et Génomique Structurales, Institut de Génétique et de Biologie Moléculaire et Cellulaire, F-67404 Illkirch, France, ^¶AstraZeneca R&D Mölndal, S-43183 Mölndal, Sweden, Universitäts-Frauenklinik, Zentrale Klinische Forschung, D-79106 Freiburg, Germany, and ^||Institut Gilbert Laustriat, University Strasbourg I, F-67412 Illkirch, France

Although structural studies on the ligand-binding domain (LBD) have established the general mode of nuclear receptor (NR)/coactivator interaction, determinants of binding specificity are only partially understood. The LBD of estrogen receptor- (ER), for example, interacts only with a region of peroxisome proliferator-activated receptor coactivator (PGC)-1, which contains the canonical LXXLL motif (NR box2), whereas the LBD of estrogen-related receptor- (ERR) also binds efficiently an untypical, LXXYL-containing region (NR box3) of PGC-1. Surprisingly, in a previous structural study, the ER LBD has been observed to bind NR box3 of transcriptional intermediary factor (TIF)-2 untypically via LXXYL, whereas the ERR LBD binds this region of TIF-2 only poorly. Here we present a new crystal structure of the ERR LBD in complex with a PGC-1 box3 peptide. In this structure, residues N-terminal of the PGC-1 LXXYL motif formed contacts with helix 4, the loop connecting helices 8 and 9, and with the C terminus of the ERR LBD. Interaction studies using wild-type and mutant PGC-1 and ERR showed that these contacts are functionally relevant and are required for efficient ERR/PGC-1 interaction. Furthermore, a structure comparison between ERR and ER and mutation analyses provided evidence that the helix 8–9 loop, which differs significantly in both nuclear receptors, is a major determinant of coactivator binding specificity. Finally, our results revealed that in ERR the helix 8–9 loop allosterically links the LBD homodimer interface with the coactivator cleft, thus providing a plausible explanation for distinct PGC-1 binding to ERR monomers and homodimers.

Received for publication, March 10, 2008

The atomic coordinates and structure factors (code 3D24) have been deposited in the Protein Data Bank, Research Collaboratory for Structural Bioinformatics, Rutgers University, New Brunswick, NJ (http://www.rcsb.org/).

^* This study was supported by CNRS, INSERM, Université Louis Pasteur, the European Commission Structural Proteomics in Europe (SPINE) (QLG2-CT-220-0098) and SPINE2-Complexes (LSHG-CT-2006-031220) under the integrated program, Quality of Life and Management of Living Resources. 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.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. S1 and S2.

¹ Current address: Diamond Light Source, Chilton, Didcot, Oxfordshire OX11 0DE, United Kingdom.

² Current address: Eurogentec, Liège Science Park, Rue Bois Saint-Jean 14, B-4102 Seraing, Belgium.

³ To whom correspondence should be addressed: Dépt. de Biologie et Génomique Structurales, Inst. de Génétique et de Biologie Moléculaire et Cellulaire, 1 rue Laurent Fries, B.P. 10142, F-67404 Illkirch, France. Tel.: 33-38865-3220; Fax: 33-38865-3276; E-mail: moras{at}igbmc.u-strasbg.fr.

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