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The AF1 and AF2 domains of the androgen receptor interact with distinct regions of SRC1 总被引:2,自引:0,他引:2
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Bevan CL Hoare S Claessens F Heery DM Parker MG 《Molecular and cellular biology》1999,19(12):8383-8392
The androgen receptor is unusual among nuclear receptors in that most, if not all, of its activity is mediated via the constitutive activation function in the N terminus. Here we demonstrate that p160 coactivators such as SRC1 (steroid receptor coactivator 1) interact directly with the N terminus in a ligand-independent manner via a conserved glutamine-rich region between residues 1053 and 1123. Although SRC1 is capable of interacting with the ligand-binding domain by means of LXXLL motifs, this interaction is not essential since an SRC1 mutant with no functional LXXLL motifs retains its ability to potentiate androgen receptor activity. In contrast, mutants lacking the glutamine-rich region are inactive, indicating that this region is both necessary and sufficient for recruitment of SRC1 to the androgen receptor. This recruitment is in direct contrast to the recruitment of SRC1 to the estrogen receptor, which requires interaction with the ligand-binding domain. 相似文献
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Molecular cloning and characterization of PELP1, a novel human coregulator of estrogen receptor alpha 总被引:7,自引:0,他引:7
Vadlamudi RK Wang RA Mazumdar A Kim Y Shin J Sahin A Kumar R 《The Journal of biological chemistry》2001,276(41):38272-38279
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The estrogen receptor enhances AP-1 activity by two distinct mechanisms with different requirements for receptor transactivation functions. 总被引:13,自引:0,他引:13
P Webb P Nguyen C Valentine G N Lopez G R Kwok E McInerney B S Katzenellenbogen E Enmark J A Gustafsson S Nilsson P J Kushner 《Molecular endocrinology (Baltimore, Md.)》1999,13(10):1672-1685
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An extended LXXLL motif sequence determines the nuclear receptor binding specificity of TRAP220 总被引:6,自引:0,他引:6
The interaction of coactivators with the ligand-binding domain of nuclear receptors (NRs) is mediated by amphipathic alpha-helices containing the signature motif LXXLL. TRAP220 contains two LXXLL motifs (LXM1 and LXM2) that are required for its interaction with NRs. Here we show that the nuclear receptor interaction domain (NID) of TRAP220 interacts weakly with Class I NRs. In contrast, SRC1 NID binds strongly to both Class I and Class II NRs. Interaction assays using nine amino acid LXXLL core motifs derived from SRC1 and TRAP220 revealed no discriminatory NR binding preferences. However, an extended LXM1 sequence containing amino acids -4 to +9, (where the first conserved leucine is +1) showed selective binding to thyroid hormone receptor and reduced binding to estrogen receptor. Replacement of either TRAP220 LXXLL motif with the corresponding 13 amino acids of SRC1 LXM2 strongly enhanced the interaction of the TRAP220 NID with the estrogen receptor. Mutational analysis revealed combinatorial effects of the LXM1 core and flanking sequences in the determination of the NR binding specificity of the TRAP220 NID. In contrast, a mutation that increased the spacing between TRAP220 LXM1 and LXM2 had little effect on the binding properties of this domain. Thus, a 13-amino acid sequence comprising an extended LXXLL motif acts as the key determinant of the NR binding specificity of TRAP220. Finally, we show that the NR binding specificity of full-length TRAP220 can be altered by swapping extended LXM sequences. 相似文献
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Webb P Valentine C Nguyen P Price RH Marimuthu A West BL Baxter JD Kushner PJ 《Nuclear receptor》2003,1(1):4
Nuclear receptors (NRs) usually bind the corepressors N-CoR and SMRT in the absence of ligand or in the presence of antagonists. Agonist binding leads to corepressor release and recruitment of coactivators. Here, we report that estrogen receptor beta (ERbeta) binds N-CoR and SMRT in the presence of agonists, but not antagonists, in vitro and in vivo. This ligand preference differs from that of ERalpha interactions with corepressors, which are inhibited by estradiol, and resembles that of ERbeta interactions with coactivators. ERbeta /N-CoR interactions involve ERbeta AF-2, which also mediates coactivator recognition. Moreover, ERbeta recognizes a sequence (PLTIRML) in the N-CoR C-terminus that resembles coactivator LXXLL motifs. Inhibition of histone deacetylase activity specifically potentiates ERbeta LBD activity, suggesting that corepressors restrict the activity of AF-2. We conclude that the ER isoforms show completely distinct modes of interaction with a physiologically important corepressor and discuss our results in terms of ER isoform specificity in vivo. 相似文献
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