JBC Transcription and Nuclear Factor Monoclonals

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Originally published In Press as doi:10.1074/jbc.M210910200 on December 26, 2002

J. Biol. Chem., Vol. 278, Issue 10, 8637-8644, March 7, 2003
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Ligand and Coactivator Identity Determines the Requirement of the Charge Clamp for Coactivation of the Peroxisome Proliferator-activated Receptor gamma *

Yifei Wu, William W. Chin, Yong Wang, and Thomas P. BurrisDagger

From the Lilly Research Laboratories, Lilly Corporate Center, Indianapolis, Indiana 46285

The activation function 2 (AF-2)-dependent recruitment of coactivator is essential for gene activation by nuclear receptors. We show that the peroxisome proliferator-activated receptor gamma  (PPARgamma ) (NR1C3) coactivator-1 (PGC-1) requires both the intact AF-2 domain of PPARgamma and the LXXLL domain of PGC-1 for ligand-dependent and ligand-independent interaction and coactivation. Although the AF-2 domain of PPARgamma is absolutely required for PGC-1-mediated coactivation, this coactivator displayed a unique lack of requirement for the charge clamp of the ligand-binding domain of the receptor that is thought to be essential for LXXLL motif recognition. The mutation of a single serine residue adjacent to the core LXXLL motif of PGC-1 led to restoration of the typical charge clamp requirement. Thus, the unique structural features of the PGC-1 LXXLL motif appear to mediate an atypical mode of interaction with PPARgamma . Unexpectedly, we discovered that various ligands display variability in terms of their requirement for the charge clamp of PPARgamma for coactivation by PGC-1. This ligand-selective variable requirement for the charge clamp was coactivator-specific. Thus, distinct structural determinants, which may be unique for a particular ligand, are utilized by the receptor to recognize the coactivator. Our data suggest that even subtle differences in ligand structure are perceived by the receptor and translated into a unique display of the coactivator-binding surface of the ligand-binding domain, allowing for differential recognition of coactivators that may underlie distinct pharmacological profiles observed for ligands of a particular nuclear receptor.

* The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Dagger To whom correspondence should be addressed: Gene Regulation, Bone and Inflammation Research, DC 0434, Lilly Research Laboratories, Lilly Corporate Center, Indianapolis, IN 46285. Tel.: 317-433-4962; Fax: 317-276-1414; E-mail: burris_thomas_p@lilly.com.

Copyright © 2003 by The American Society for Biochemistry and Molecular Biology, Inc.
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