Control of glucocorticoid and progesterone receptor subcellular localization by the ligand-binding domain is mediated by distinct interactions with tetratricopeptide repeat proteins.
Control of glucocorticoid and progesterone receptor subcellular localization by the ligand-binding domain is mediated by distinct interactions with tetratricopeptide repeat proteins.
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DOI：
10.1021/bi8011862
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发表时间：
2008-09-30
期刊：
影响因子：
2.9
通讯作者：
Sanchez, Edwin R.
中科院分区：
文献类型：
--
作者：
Banerjee, Ananya;Periyasamy, Sumudra;Wolf, Irene M.;Hinds, Terry D., Jr.;Yong, Weidong;Shou, Weinian;Sanchez, Edwin R.
TPR蛋白FKBP52， FKBP51， Cyp40和PP5在类固醇受体（SR）复合物中被发现，但它们的受体特异性偏好和作用尚不清楚。我们通过检查所有四种tpr对糖皮质激素（GR）和孕激素（PR）受体定位特性的贡献，采取了系统的方法来解决这个问题。L929细胞的GR以含有PP5和FKBP51的复合体形式存在于细胞质中，而WCL2细胞的GR以细胞核形式存在，含有PP5和FKBP52。Cyp40在两种细胞系中均不与GR相互作用。为了测试FKBP相互作用是否决定了定位，我们在WCL2细胞中过表达flag标记的FKBP51，在L929细胞中过表达Flag-FKBP52。在WCL2细胞中，GR向更大的细胞质定位转变，这与Flag-FKBP51的募集有关。相反，Flag-FKBP52没有被募集到L929细胞的GR中，并且没有观察到定位的变化，这表明细胞类型特异性机制和TPR丰度都有助于SR/TPR相互作用。作为进一步的测试，GR-GFP和PR-GFP构建体在COS细胞中表达。GR-GFP定位于细胞质，PR-GFP主要位于细胞核。与L929细胞相似，COS中的GR与PP5和FKBP51相互作用，PR与FKBP52相互作用。对GR/PR嵌合结构体的分析表明，每种受体的配体结合结构域决定了TPR的特异性和定位。最后，我们分析了完全缺乏TPR的细胞中GR和PR的定位。FKBP52 KO细胞中的PR完全转移到细胞质中，而FKBP51 KO和PP5 KO细胞中的GR则适度转移到细胞核中，这表明两种tpr都参与了GR的定位。我们的研究结果表明，SRs对TPR蛋白有明显的偏好——这种特性存在于LBD中，现在可以解释受体亚细胞定位的长期差异。
The TPR proteins FKBP52, FKBP51, Cyp40 and PP5 are found in steroid receptor (SR) complexes but their receptor-specific preferences and roles remain unresolved. We have undertaken a systematic approach to this problem by examining the contribution of all four TPRs to the localization properties of glucocorticoid (GR) and progesterone (PR) receptors. The GR of L929 cells was found in the cytoplasm in a complex containing PP5 and FKBP51, while GR of WCL2 cells was nuclear and contained PP5 and FKBP52. Cyp40 did not interact with GR in either cell line. To test whether FKBP interaction determined localization, we over-expressed Flag-tagged FKBP51 in WCL2 cells and Flag-FKBP52 in L929 cells. In WCL2 cells, GR showed a shift to greater cytoplasmic localization that correlated with recruitment of Flag-FKBP51. In contrast, Flag-FKBP52 was not recruited to GR of L929 cells and no change in localization was observed, suggesting that both cell-type specific mechanisms and TPR abundance contribute to the SR/TPR interaction. As a further test, GR-GFP and PR-GFP constructs were expressed in COS cells. GR-GFP localized to the cytoplasm, while PR-GFP was predominantly nuclear. Similar to L929 cells, GR in COS interacted with PP5 and FKBP51, while PR interacted with FKBP52. Analysis of GR/PR chimeric constructs revealed that the ligand-binding domain of each receptor determines both TPR specificity and localization. Lastly, we analyzed GR and PR localization in cells completely lacking TPR. PR in FKBP52 KO cells showed a complete shift to the cytoplasm, while GR in FKBP51 KO and PP5 KO cells showed a moderate shift to the nucleus, indicating that both TPRs contribute to GR localization. Our results demonstrate that SRs have distinct preferences for TPR proteins – a property that resides in the LBD and which can now explain long-standing differences in receptor subcellular localization.
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影响因子：
--
作者：
CZAR, MJ;LYONS, RH;PRATT, WB
通讯作者：
PRATT, WB
影响因子：
11.4
作者：
PICARD, D;YAMAMOTO, KR
通讯作者：
YAMAMOTO, KR
DOI：
10.1073/pnas.59.2.632
发表时间：
1968-01-01
影响因子：
11.1
作者：
JENSEN, EV;SUZUKI, T;DESOMBRE, ER
通讯作者：
DESOMBRE, ER
DOI：
10.1073/pnas.1732707100
发表时间：
2003-08-19
影响因子：
11.1
作者：
Mulac-Jericevic, B;Lydon, JP;Conneely, OM
通讯作者：
Conneely, OM
影响因子：
--
作者：
HIRST, MA;NORTHROP, JP;RINGOLD, GM
通讯作者：
RINGOLD, GM