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富含脯氨酸的PNRC的SH3结合基序与雌激素受体α之间相互作用的分子基础。

The molecular basis of the interaction between the proline-rich SH3-binding motif of PNRC and estrogen receptor alpha.

作者信息

Zhou Dujin, Ye Jing Jing, Li Yuping, Lui Ki, Chen Shiuan

机构信息

Department of Surgical Research, Beckman Research Institute of City of Hope, 1450 East Duarte Road, Duarte, CA 91010, USA.

出版信息

Nucleic Acids Res. 2006;34(20):5974-86. doi: 10.1093/nar/gkl764. Epub 2006 Oct 26.

DOI:10.1093/nar/gkl764
PMID:17068076
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC1635328/
Abstract

PNRC and PNRC2 are members of a new family of nuclear receptor coactivators. We systematically determined the molecular basis and the structure/function relationship for the PNRC-ERalpha interaction. PNRC was found to interact with ERalpha mainly through its C-terminus region, amino acids 270-327, and an SH3-binding motif within this region was shown to be essential for PNRC to interact with and function as coactivator of ERalpha. The importance of the flanking sequences of SH3-binding motif in the interaction between PNRC and ERalpha was also investigated. The PNRC-interacting domain(s) on ERalpha was also mapped. PNRC was found to interact with both AF1 and LBD of ERalpha, and to function as a coactivator for both AF1 and AF2 transactivation functions. The interaction of ERalpha mutants, I358R, K362A, V376R, L539R and E542K, with PNRC/PNRC2 was further investigated. ERalpha/HBD/V376R could bind to PNRC or PNRC2, with similar affinity as wild-type ERalpha/HBD, and the transactivation activity of ERalpha/V376R was enhanced 5-fold by PNRC. Since GRIP1, a well-characterized coactivator, was found not to be able to enhance the transactivation function of this mutant, our results indicate that the PNRC-ERalpha interaction interface is not exactly identical to that of GRIP1-ERalpha interaction.

摘要

PNRC和PNRC2是核受体共激活因子新家族的成员。我们系统地确定了PNRC与雌激素受体α（ERα）相互作用的分子基础及结构/功能关系。发现PNRC主要通过其C末端区域（氨基酸270 - 327）与ERα相互作用，并且该区域内的一个SH3结合基序被证明对于PNRC与ERα相互作用并作为其共激活因子发挥功能至关重要。还研究了SH3结合基序侧翼序列在PNRC与ERα相互作用中的重要性。同时也绘制了ERα上与PNRC相互作用的结构域。发现PNRC与ERα的AF1和配体结合结构域（LBD）均相互作用，并作为AF1和AF2反式激活功能的共激活因子发挥作用。进一步研究了ERα突变体I358R、K362A、V376R、L539R和E542K与PNRC/PNRC2的相互作用。ERα/HBD/V376R能够与PNRC或PNRC2结合，亲和力与野生型ERα/HBD相似，并且PNRC可使ERα/V376R的反式激活活性增强5倍。由于已充分表征的共激活因子GRIP1不能增强该突变体的反式激活功能，我们的结果表明PNRC - ERα相互作用界面与GRIP1 - ERα相互作用界面并不完全相同。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/824c/1694047/02da6565cba0/gkl764f6.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/824c/1694047/84e56175246f/gkl764f5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/824c/1694047/02da6565cba0/gkl764f6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/824c/1694047/9d911722c072/gkl764f1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/824c/1694047/7a214e93ef55/gkl764f2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/824c/1694047/302cd57f3432/gkl764f3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/824c/1694047/9433f13c2f81/gkl764f4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/824c/1694047/84e56175246f/gkl764f5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/824c/1694047/02da6565cba0/gkl764f6.jpg

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