Hong H, Darimont B D, Ma H, Yang L, Yamamoto K R, Stallcup M R
Department of Pathology, University of Southern California, Los Angeles, California 90033, USA.
J Biol Chem. 1999 Feb 5;274(6):3496-502. doi: 10.1074/jbc.274.6.3496.
Transcriptional coactivators of the p160 family (SRC-1, GRIP1, and p/CIP) associate with DNA-bound nuclear receptors (NRs) and help the NRs to recruit an active transcription initiation complex to the promoters of target genes. Previous studies have demonstrated the importance of the NR interaction domain (NID) of p160 proteins containing three NR box motifs (LXXLL) for the interaction with the hormone-binding domains of NRs. Here we report that, in addition to NID, another region of coactivator GRIP1 (amino acids 1011-1121), called the auxiliary NID (NIDaux), is required in vitro and in vivo for efficient interaction with a subset of NRs, including the glucocorticoid receptor (GR), androgen receptor, and retinoic acid receptor alpha. A second group of NRs, which includes the progesterone receptor, retinoid X receptor alpha, thyroid hormone receptor beta1, and vitamin D receptor, required only NID for efficient interaction. For binding to GR, the NID and NIDaux of GRIP1 must act in cis, but deletion of up to 144 amino acids between the two regions did not reduce binding efficiency. Amino acids 1011-1121 of GRIP1 also contain a p300 interaction domain, but mutational analysis indicated that the p300 interaction function within this region is separable from the ability to contribute to GR hormone-binding domain binding. SRC-1 lacks an NIDaux activity equivalent to that in GRIP1.
p160家族的转录共激活因子（SRC-1、GRIP1和p/CIP）与结合DNA的核受体（NRs）相关联，并帮助NRs招募活性转录起始复合物至靶基因的启动子区域。先前的研究已证明，含有三个NR框基序（LXXLL）的p160蛋白的NR相互作用结构域（NID）对于与NRs的激素结合结构域相互作用的重要性。在此我们报告，除了NID之外，共激活因子GRIP1的另一个区域（氨基酸1011 - 1121），称为辅助NID（NIDaux），在体外和体内对于与包括糖皮质激素受体（GR）、雄激素受体和视黄酸受体α在内的一部分NRs进行有效相互作用是必需的。第二组NRs，包括孕激素受体、视黄酸X受体α、甲状腺激素受体β1和维生素D受体，仅需要NID进行有效相互作用。对于与GR的结合，GRIP1的NID和NIDaux必须顺式作用，但两个区域之间缺失多达144个氨基酸并不降低结合效率。GRIP1的氨基酸1011 - 1121还包含一个p300相互作用结构域，但突变分析表明该区域内的p300相互作用功能与促进GR激素结合结构域结合的能力是可分离的。SRC-1缺乏与GRIP1中相当的NIDaux活性。
