Journal
JOURNAL OF BIOLOGICAL CHEMISTRY
Volume 285, Issue 5, Pages 3126-3132Publisher
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M109.055095
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Funding
- Japan Society for the Promotion of Science [18GS0316]
- Grants-in-Aid for Scientific Research [18GS0316, 21390031] Funding Source: KAKEN
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The important roles of a nuclear receptor peroxisome proliferator-activated receptor gamma (PPAR gamma) are widely accepted in various biological processes as well as metabolic diseases. Despite the worldwide quest for pharmaceutical manipulation of PPAR gamma 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 PPAR gamma activity by a peptidyl-prolyl isomerase, Pin1. Pin1 interacts with the phosphorylated AF-1 domain, thereby inhibiting the polyubiquitination of PPAR gamma. 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 PPAR gamma-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 PPAR gamma.
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