The molecular basis of the interaction between the proline-rich SH3-binding motif of PNRC and estrogen receptor alpha.
The molecular basis of the interaction between the proline-rich SH3-binding motif of PNRC and estrogen receptor alpha.
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DOI：
10.1093/nar/gkl764
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发表时间：
2006
影响因子：
14.9
通讯作者：
Chen S
中科院分区：
文献类型：
--
作者：
Zhou D;Ye JJ;Li Y;Lui K;Chen S
PNRC和PNRC2是一个新的核受体共激活因子家族的成员。我们系统地确定了PNRC-ERα相互作用的分子基础和结构/功能关系。研究发现PNRC主要通过其c端区域270-327氨基酸与ERα相互作用，该区域的sh3结合基序是PNRC与ERα相互作用和作为ERα共激活子的必要条件。我们还研究了sh3结合基序的侧翼序列在PNRC与ERα相互作用中的重要性。ERα上的pnrc相互作用域(s)也被绘制出来。发现PNRC与ERα的AF1和LBD相互作用，并作为AF1和AF2交互激活功能的辅激活因子。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可与PNRC或PNRC2结合，与野生型ERα/HBD具有相似的亲和力，经PNRC处理后ERα/V376R的活化活性提高了5倍。由于GRIP1是一种特性良好的共激活子，但我们发现它不能增强该突变体的转激活功能，因此我们的研究结果表明，pnrc - er - α相互作用界面与GRIP1 - er - α相互作用界面并不完全相同。
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–ERα interaction. PNRC was found to interact with ERα 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 ERα. The importance of the flanking sequences of SH3-binding motif in the interaction between PNRC and ERα was also investigated. The PNRC-interacting domain(s) on ERα was also mapped. PNRC was found to interact with both AF1 and LBD of ERα, and to function as a coactivator for both AF1 and AF2 transactivation functions. The interaction of ERα mutants, I358R, K362A, V376R, L539R and E542K, with PNRC/PNRC2 was further investigated. ERα/HBD/V376R could bind to PNRC or PNRC2, with similar affinity as wild-type ERα/HBD, and the transactivation activity of ERα/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–ERα interaction interface is not exactly identical to that of GRIP1–ERα interaction.