Journal
JOURNAL OF BIOLOGICAL CHEMISTRY
Volume 282, Issue 13, Pages 9666-9677Publisher
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M610523200
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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 alpha (PPAR alpha) constitutive and ligand-dependent transcriptional activity. Functional assays of the activity of PPARa 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 alpha 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 alpha transcription activation potential. Finally, we disclose important functions of residues in PPAR alpha 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 alpha constitutive activity, without changing PPARa ligand-dependent activation potential.
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