Alteration of a single amino acid in peroxisome proliferator-activated receptor-α (PPARα) generates a PPARδ phenotype

Ichiro Takada, Ruth T. Yu, H. Eric Xu, Millard H. Lambert, Valerie G. Montana, Steven A. Kliewer, Ronald M. Evans, Kazuhiko Umesono

Research output: Contribution to journalArticle

66 Citations (Scopus)

Abstract

Three pharmacologically important nuclear receptors, the peroxisome proliferator-activated receptors (PPARs α, γ, and δ), mediate key transcriptional responses involved in lipid homeostasis. The PPARα and γ subtypes are well conserved from Xenopus to man, but the β/δ subtypes display substantial species variations in both structure and ligand activation profiles. Characterization of the avian cognates revealed a close relationship between chick (c) α and γ subtypes to their mammalian counterparts, whereas the third chicken subtype was intermediate to Xenopus (x) β and mammalian δ, establishing that β and δ are orthologs. Like xPPARβ, cPPARβ responded efficiently to hypolipidemic compounds that fail to activate the human counterpart. This provided the opportunity to address the pharmacological problem as to how drug selectivity is achieved and the more global evolutionary question as to the minimal changes needed to generate a new class of receptor. X-ray crystallography and chimeric analyses combined with site-directed mutagenesis of avian and mammalian cognates revealed that a Met to Val change at residue 417 was sufficient to switch the human and chick phenotype. These results establish that the genetic drive to evolve a novel and functionally selectable receptor can be modulated by a single amino acid change and suggest how nuclear receptors can accommodate natural variation in species physiology.

Original languageEnglish (US)
Pages (from-to)733-740
Number of pages8
JournalMolecular Endocrinology
Volume14
Issue number5
DOIs
StatePublished - 2000

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Peroxisome Proliferator-Activated Receptors
Cytoplasmic and Nuclear Receptors
Xenopus
Phenotype
Amino Acids
X Ray Crystallography
Site-Directed Mutagenesis
Chickens
Homeostasis
Pharmacology
Ligands
Lipids
Pharmaceutical Preparations

ASJC Scopus subject areas

  • Molecular Biology
  • Endocrinology, Diabetes and Metabolism

Cite this

Alteration of a single amino acid in peroxisome proliferator-activated receptor-α (PPARα) generates a PPARδ phenotype. / Takada, Ichiro; Yu, Ruth T.; Xu, H. Eric; Lambert, Millard H.; Montana, Valerie G.; Kliewer, Steven A.; Evans, Ronald M.; Umesono, Kazuhiko.

In: Molecular Endocrinology, Vol. 14, No. 5, 2000, p. 733-740.

Research output: Contribution to journalArticle

Takada, Ichiro ; Yu, Ruth T. ; Xu, H. Eric ; Lambert, Millard H. ; Montana, Valerie G. ; Kliewer, Steven A. ; Evans, Ronald M. ; Umesono, Kazuhiko. / Alteration of a single amino acid in peroxisome proliferator-activated receptor-α (PPARα) generates a PPARδ phenotype. In: Molecular Endocrinology. 2000 ; Vol. 14, No. 5. pp. 733-740.
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