Proline cis/trans-isomerase Pin1 regulates peroxisome proliferator- activated receptor γactivity through the direct binding to the activation function-1 domain

Yoshito Fujimoto, Takuma Shiraki, Yuji Horiuchi, Tsuyoshi Waku, Akira Shigenaga, Akira Otaka, Tsuyoshi Ikura, Kazuhiko Igarashi, Saburo Aimoto, Shin Ichi Tate, Kosuke Morikawa

Research output: Contribution to journalArticlepeer-review

29 Citations (Scopus)

Abstract

The important roles of a nuclear receptor peroxisome proliferator-activated receptor γ (PPARγ) are widely accepted in various biological processes as well as metabolic diseases. Despite the worldwide quest for pharmaceutical manipulation of PPARγ activity through the ligand-binding domain, very little information about the activation mechanism of the N-terminal activation function-1 (AF-1) domain. Here, we demonstrate the molecular and structural basis of the phosphorylation-dependent regulation of PPARγ activity by a peptidyl-prolyl isomerase, Pin1. Pin1 interacts with the phosphorylated AF-1 domain, thereby inhibiting the polyubiquitination of PPARγ. The interaction and inhibition are dependent upon the WW domain of Pin1 but are independent of peptidyl-prolyl cis/trans-isomerase activity. Gene knockdown experiments revealed that Pin1 inhibits the PPARγ-dependent gene expression in THP-1 macrophage-like cells. Thus, our results suggest that Pin1 regulates macrophage function through the direct binding to the phosphorylated AF-1 domain of PPARγ.

Original languageEnglish
Pages (from-to)3126-3132
Number of pages7
JournalJournal of Biological Chemistry
Volume285
Issue number5
DOIs
Publication statusPublished - 2010 Jan 29

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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