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Title: Structural and Biochemical Basis for the Binding Selectivity of Peroxisome Proliferator-activated Receptor [gamma] to PGC-1[alpha]

Abstract

The functional interaction between the peroxisome proliferator-activated receptor {gamma} (PPAR{gamma}) and its coactivator PGC-1{alpha} is crucial for the normal physiology of PPAR{gamma} and its pharmacological response to antidiabetic treatment with rosiglitazone. Here we report the crystal structure of the PPAR{gamma} ligand-binding domain bound to rosiglitazone and to a large PGC-1{alpha} fragment that contains two LXXLL-related motifs. The structure reveals critical contacts mediated through the first LXXLL motif of PGC-1{alpha} and the PPAR{gamma} coactivator binding site. Through a combination of biochemical and structural studies, we demonstrate that the first LXXLL motif is the most potent among all nuclear receptor coactivator motifs tested, and only this motif of the two LXXLL-related motifs in PGC-1{alpha} is capable of binding to PPAR{gamma}. Our studies reveal that the strong interaction of PGC-1{alpha} and PPAR{gamma} is mediated through both hydrophobic and specific polar interactions. Mutations within the context of the full-length PGC-1{alpha} indicate that the first PGC-1{alpha} motif is necessary and sufficient for PGC-1{alpha} to coactivate PPAR{gamma} in the presence or absence of rosiglitazone. These results provide a molecular basis for specific recruitment and functional interplay between PPAR{gamma} and PGC-1{alpha} in glucose homeostasis and adipocyte differentiation.

Authors:
; ; ; ;  [1]
  1. Pitt
Publication Date:
Research Org.:
Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
Sponsoring Org.:
USDOE
OSTI Identifier:
1006726
Resource Type:
Journal Article
Journal Name:
J. Biol. Chem.
Additional Journal Information:
Journal Volume: 283; Journal Issue: (27) ; 07, 2008; Journal ID: ISSN 0021-9258
Country of Publication:
United States
Language:
ENGLISH
Subject:
72 PHYSICS OF ELEMENTARY PARTICLES AND FIELDS; CRYSTAL STRUCTURE; FUNCTIONALS; GLUCOSE; HOMEOSTASIS; MUTATIONS; PHYSIOLOGY; STRONG INTERACTIONS

Citation Formats

Li, Yong, Kovach, Amanda, Suino-Powell, Kelly, Martynowski, Dariusz, Xu, H Eric, and Van Andel). Structural and Biochemical Basis for the Binding Selectivity of Peroxisome Proliferator-activated Receptor [gamma] to PGC-1[alpha]. United States: N. p., 2008. Web. doi:10.1074/jbc.M802040200.
Li, Yong, Kovach, Amanda, Suino-Powell, Kelly, Martynowski, Dariusz, Xu, H Eric, & Van Andel). Structural and Biochemical Basis for the Binding Selectivity of Peroxisome Proliferator-activated Receptor [gamma] to PGC-1[alpha]. United States. https://doi.org/10.1074/jbc.M802040200
Li, Yong, Kovach, Amanda, Suino-Powell, Kelly, Martynowski, Dariusz, Xu, H Eric, and Van Andel). 2008. "Structural and Biochemical Basis for the Binding Selectivity of Peroxisome Proliferator-activated Receptor [gamma] to PGC-1[alpha]". United States. https://doi.org/10.1074/jbc.M802040200.
@article{osti_1006726,
title = {Structural and Biochemical Basis for the Binding Selectivity of Peroxisome Proliferator-activated Receptor [gamma] to PGC-1[alpha]},
author = {Li, Yong and Kovach, Amanda and Suino-Powell, Kelly and Martynowski, Dariusz and Xu, H Eric and Van Andel)},
abstractNote = {The functional interaction between the peroxisome proliferator-activated receptor {gamma} (PPAR{gamma}) and its coactivator PGC-1{alpha} is crucial for the normal physiology of PPAR{gamma} and its pharmacological response to antidiabetic treatment with rosiglitazone. Here we report the crystal structure of the PPAR{gamma} ligand-binding domain bound to rosiglitazone and to a large PGC-1{alpha} fragment that contains two LXXLL-related motifs. The structure reveals critical contacts mediated through the first LXXLL motif of PGC-1{alpha} and the PPAR{gamma} coactivator binding site. Through a combination of biochemical and structural studies, we demonstrate that the first LXXLL motif is the most potent among all nuclear receptor coactivator motifs tested, and only this motif of the two LXXLL-related motifs in PGC-1{alpha} is capable of binding to PPAR{gamma}. Our studies reveal that the strong interaction of PGC-1{alpha} and PPAR{gamma} is mediated through both hydrophobic and specific polar interactions. Mutations within the context of the full-length PGC-1{alpha} indicate that the first PGC-1{alpha} motif is necessary and sufficient for PGC-1{alpha} to coactivate PPAR{gamma} in the presence or absence of rosiglitazone. These results provide a molecular basis for specific recruitment and functional interplay between PPAR{gamma} and PGC-1{alpha} in glucose homeostasis and adipocyte differentiation.},
doi = {10.1074/jbc.M802040200},
url = {https://www.osti.gov/biblio/1006726}, journal = {J. Biol. Chem.},
issn = {0021-9258},
number = (27) ; 07, 2008,
volume = 283,
place = {United States},
year = {Wed Jul 23 00:00:00 EDT 2008},
month = {Wed Jul 23 00:00:00 EDT 2008}
}