A signature motif in transcriptional co-activators mediates binding to nuclear receptor
A signature motif in transcriptional co-activators mediates binding to nuclear receptor
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DOI：
10.1038/42750
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发表时间：
1997-06-12
期刊：
影响因子：
64.8
通讯作者：
Parker, MG
中科院分区：
文献类型：
--
作者：
Heery, DM;Kalkhoven, E;Parker, MG
亲脂性激素、类维生素A和维生素与核受体超家族成员的结合改变了这些受体的DNA结合和转录特性，导致靶基因的激活或抑制（1，2）。配体结合诱导核受体的构象变化并促进其与包括SRC 1/p160在内的多种核蛋白的结合（参考文献3-5），TIF-2/GRIP-1（参考文献6、7）和CBP/p300（参考文献4，5，8，9），以及RIP-140（参考文献10）、TIF-1（参考文献II）和TRIP-1/SUG-1（参考文献12，13），其功能尚不清楚。在这里，我们报告说，RIP-140、SRC-1和CBP中存在的短序列基序LXXLL（其中Lis leucine，X是任何氨基酸）对于介导这些蛋白质与配体核受体的结合是必要且足够的。我们表明SRC-1结合雌激素受体并增强其转录活性的能力取决于LXXLL基序的完整性和雌激素受体的保守螺旋（螺旋12）中的关键疏水残基，这是其配体诱导的激活功能所需的（14）。我们提出LXXLL基序是一个签名序列，促进不同蛋白质与核受体的相互作用，因此是一个新的核蛋白家族的定义特征。
The binding of lipophilic hormones, retinoids and vitamins to members of the nuclear-receptor superfamily modifies the DNA-binding and transcriptional properties of these receptors, resulting in the activation or repression of target genes(1,2). Ligand binding induces conformational changes in nuclear receptors and promotes their association with a diverse group of nuclear proteins, including SRC1/p160 (refs 3-5), TIF-2/GRIP-1 (refs 6, 7) and CBP/p300 (refs 4, 5, 8, 9) which function as co-activators of transcription, and RIP-140 (ref. 10), TIF-1 (ref. II) and TRIP-1/SUG-1 (refs 12, 13) whose functions are unclear. Here we report that a short sequence motif LXXLL (where Lis leucine and X is any amino acid) present in RIP-140, SRC-1 and CBP is necessary and sufficient to mediate the binding of these proteins to liganded nuclear receptors. We show that the ability of SRC-1 to bind the oestrogen receptor and enhance its transcriptional activity is dependent upon the integrity of the LXXLL motifs and on key hydrophobic residues in a conserved helix (helix 12) of the oestrogen receptor that are required for its ligand-induced activation function(14). We propose that the LXXLL motif is a signature sequence that facilitates the interaction of different proteins with nuclear receptors, and is thus a defining feature of a new family of nuclear proteins.