Proline cis/trans-isomerase Pin1 regulates peroxisome proliferator-activated receptor gamma activity through the direct binding to the activation function-1 domain.
The important roles of a nuclear receptor peroxisome proliferator-activated receptor gamma (PPARgamma) are widely accepted in various biological processes as well as metabolic diseases. Despite the worldwide quest for pharmaceutical manipulation of PPARgamma 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 PPARgamma activity by a peptidyl-prolyl isomerase, Pin1. Pin1 interacts with the phosphorylated AF-1 domain, thereby inhibiting the polyubiquitination of PPARgamma. 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 PPARgamma-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 PPARgamma.
Fujimoto
Yoshito
Y
The Takara-Bio Endowed Division, Department of Biomolecular Recognition, Institute for Protein Research, Osaka University, Open Laboratories of Advanced Bioscience and Biotechnology, 6-2-3 Furuedai, Suita, Osaka 565-0874, Japan.
Shiraki
Takuma
T
Horiuchi
Yuji
Y
Waku
Tsuyoshi
T
Shigenaga
Akira
A
Otaka
Akira
A
Ikura
Tsuyoshi
T
Igarashi
Kazuhiko
K
Aimoto
Saburo
S
Tate
Shin-ichi
S
Morikawa
Kosuke
K
D000818:Animals; D002460:Cell Line; D006801:Humans; D008264:Macrophages / Q000378:metabolism; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D009154:Mutation; D000072340:NIMA-Interacting Peptidylprolyl Isomerase; D047495:PPAR gamma / Q000378:metabolism*; D019696:Peptidylprolyl Isomerase / Q000378:metabolism*; D010766:Phosphorylation; D011392:Proline / Q000737:chemistry*; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D011994:Recombinant Proteins / Q000737:chemistry; D020349:Surface Plasmon Resonance
D000072340:NIMA-Interacting Peptidylprolyl Isomerase; D047495:PPAR gamma; D011994:Recombinant Proteins; D011392:Proline; C000606846:PIN1 protein, human; D019696:Peptidylprolyl Isomerase; C000606850:Pin1 protein, mouse