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Papers In Press, published online ahead of print December 26, 2002
Lilly Research Laboratories, Indianapolis, IN 46285
Corresponding Author: burris_thomas_p{at}lilly.com
The activation function 2 (AF-2)-dependent recruitment of coactivator is essential for gene activation by nuclear receptors (NRs). We show that the peroxisome proliferator-activated receptor
J. Biol. Chem, 10.1074/jbc.M210910200
Submitted on October 24, 2002
Revised on December 5, 2002
Accepted on December 25, 2002
Ligand and coactivator identity determines the requirement of the charge clamp for coactivation of the peroxisome proliferator-activated receptor
(PPAR ;NR1C3) coactivator-1 (PGC-1) coactivation of PPAR requires both the intact AF-2 domain of PPAR and the LXXLL domain of PGC-1 for ligand-dependent and –independent interaction and coactivation. Although the AF-2 domain of PPARg 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 (LBD) of the receptor that is thought to be essential for LXXLL motif recognition. Mutation of a single serine residue adjacent to the core LXXLL motif of PGC-1 lead to restoration of the typical charge clamp requirement. Thus, unique structural features of the PGC-1 LXXLL motif appear to mediate an atypical mode of interaction with PPAR . Unexpectedly, we discovered that various ligands display variability in terms of their requirement for the charge clamp of PPARg 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 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 LBD allowing for differential recognition of coactivators that may underlie distinct pharmacological profiles observed for ligands of a particular nuclear receptor.
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