Heery D M, Kalkhoven E, Hoare S, Parker M G
Molecular Endocrinology Laboratory, Imperial Cancer Research Fund, London, UK.
Nature. 1997 Jun 12;387(6634):733-6. doi: 10.1038/42750.
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. Ligand binding induces conformational changes in nuclear receptors and promotes their association with a diverse group of nuclear proteins, including SRC-1/p160, TIF-2/GRIP-1 and CBP/p300 which function as co-activators of transcription, and RIP-140, TIF-1 and TRIP-1/SUG-1 whose functions are unclear. Here we report that a short sequence motif LXXLL (where L is 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. 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.
亲脂性激素、类视黄醇和维生素与核受体超家族成员的结合会改变这些受体的DNA结合和转录特性，从而导致靶基因的激活或抑制。配体结合会诱导核受体的构象变化，并促进它们与多种核蛋白的结合，包括作为转录共激活因子的SRC-1/p160、TIF-2/GRIP-1和CBP/p300，以及功能尚不清楚的RIP-140、TIF-1和TRIP-1/SUG-1。我们在此报告，RIP-140、SRC-1和CBP中存在的短序列基序LXXLL（其中L为亮氨酸，X为任意氨基酸）对于介导这些蛋白质与配体化核受体的结合是必要且充分的。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基序的完整性以及雌激素受体保守螺旋（螺旋12）中的关键疏水残基，这些残基是其配体诱导激活功能所必需的。我们提出，LXXLL基序是一个特征序列，有助于不同蛋白质与核受体相互作用，因此是一类新的核蛋白的一个决定性特征。
