Proline cis/trans-Isomerase Pin1 Regulates Peroxisome Proliferator-activated Receptor γ Activity through the Direct Binding to the Activation Function-1 Domain

被引：35

作者：

Fujimoto, Yoshito ^{[1
]}

Shiraki, Takuma ^{[1
,2
]}

Horiuchi, Yuji ^{[3
]}

Waku, Tsuyoshi ^{[1
]}

Shigenaga, Akira ^{[4
,5
]}

Otaka, Akira ^{[4
,5
]}

Ikura, Tsuyoshi ^{[2
]}

Igarashi, Kazuhiko ^{[2
]}

Aimoto, Saburo ^{[6
]}

Tate, Shin-ichi ^{[3
]}

Morikawa, Kosuke ^{[1
]}

机构：

[1] Osaka Univ, Open Labs Adv Biosci & Biotechnol, Takara Bio Endowed Div, Dept Biomol Recognit,Inst Prot Res, Osaka 5650874, Japan

[2] Tohoku Univ, Dept Biochem, Grad Sch Med, Aoba Ku, Sendai, Miyagi 9808575, Japan

[3] Hiroshima Univ, Grad Sch Sci, Dept Math & Life Sci, Higashihiroshima 7398526, Japan

[4] Univ Tokushima, Inst Hlth Biosci, Tokushima 7708505, Japan

[5] Univ Tokushima, Grad Sch Pharmaceut Sci, Tokushima 7708505, Japan

[6] Osaka Univ, Inst Prot Res, Div Prot Chem, Lab Prot Organ Chem, Suita, Osaka 5650871, Japan

来源：

JOURNAL OF BIOLOGICAL CHEMISTRY | 2010年 / 285卷 / 05期

基金：

日本学术振兴会;

关键词：

PPAR-GAMMA; PROTEIN AP2; PHOSPHORYLATION; GENE; DIFFERENTIATION; INHIBITION; EXPRESSION; ADIPOGENESIS; METABOLISM; LIGANDS;

D O I：

10.1074/jbc.M109.055095

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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.

引用

页码：3126 / 3132

页数：7

共 30 条

[1] Transcriptional activation by peroxisome proliferator-activated receptor gamma is inhibited by phosphorylation at a consensus mitogen-activated protein kinase site [J].