Molecular determinants of the balance between co-repressor and co-activator recruitment to the retinoic acid receptor

被引:29
作者
Benko, S
Love, JD
Beládi, M
Schwabe, JWR
Nagy, L
机构
[1] Univ Debrecen, Med & Hlth Sci Ctr, Res Ctr Mol Med, Dept Biochem & Mol Biol, H-4012 Debrecen, Hungary
[2] MRC, Mol Biol Lab, Cambridge CB2 2QH, England
关键词
D O I
10.1074/jbc.M306199200
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
The repressive and activating states of nuclear hormone receptors are achieved through the recruitment of cofactor proteins. The binding of co-repressors and coactivators is believed to be mutually exclusive and principally regulated by ligand binding. To understand the molecular determinants of the switch induced by ligand in the retinoic acid receptor and in particular the intrinsic role of the ligand binding domain (LBD) in cofactor binding and release, we carried out extensive mutational analysis of surface residues of the LBD. As seen previously we found that co-repressor and co-activator molecules bind to overlapping docking sites on the surface of the retinoic acid receptor alpha LBD. Perturbation of this surface impaired both co- activator and co- repressor association resulting in a transcriptionally inert receptor. Unexpectedly mutation of two residues, Trp-225 and Ala-392, which lie outside the docking site, had opposite effects on co- activator and co- repressor binding. W225A was a constitutive repressor that failed to bind co- activator and exhibited an increased, and ligand-insensitive, interaction with co- repressor. A392R, on the other hand, had reduced affinity for co- repressors and increased affinity for co- activators and behaved as a constitutive, but still ligand-inducible, activator. Analysis of known structures showed that these mutations lie in the proximity of helix 12 (H12), and their effects are likely to be the result of perturbations in the behavior of H12. These data suggest that residues in the close vicinity of H12 regulate cofactor affinity and determine the basal activity of receptors.
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页码:43797 / 43806
页数:10
相关论文
共 58 条
  • [41] The transcriptional coactivators p300 and CBP are histone acetyltransferases
    Ogryzko, VV
    Schiltz, RL
    Russanova, V
    Howard, BH
    Nakatani, Y
    [J]. CELL, 1996, 87 (05) : 953 - 959
  • [42] ONATE SA, 1995, SCIENCE, V270, P1354
  • [43] Molecular determinants of nuclear receptor-corepressor interaction
    Perissi, V
    Staszewski, LM
    McInerney, EM
    Kurokawa, R
    Krones, A
    Rose, DW
    Lambert, MH
    Milburn, MV
    Glass, CK
    Rosenfeld, MG
    [J]. GENES & DEVELOPMENT, 1999, 13 (24) : 3198 - 3208
  • [44] Structural aspects of agonism and antagonism in the oestrogen receptor
    Pike, ACW
    Brzozowski, AM
    Walton, J
    Hubbard, RE
    Bonn, T
    Gustafsson, JÅ
    Carlquist, M
    [J]. BIOCHEMICAL SOCIETY TRANSACTIONS, 2000, 28 : 396 - 400
  • [45] The DRIP complex and SRC-1/p160 coactivators share similar nuclear receptor binding determinants but constitute functionally distinct complexes
    Rachez, C
    Gamble, M
    Chang, CPB
    Atkins, GB
    Lazar, MA
    Freedman, LP
    [J]. MOLECULAR AND CELLULAR BIOLOGY, 2000, 20 (08) : 2718 - 2726
  • [46] A novel protein complex that interacts with the vitamin D3 receptor in a ligand-dependent manner and enhances VDR transactivation in a cell-free system
    Rachez, C
    Suldan, Z
    Ward, J
    Chang, CPB
    Burakov, D
    Erdjument-Bromage, H
    Tempst, P
    Freedman, LP
    [J]. GENES & DEVELOPMENT, 1998, 12 (12) : 1787 - 1800
  • [47] CRYSTAL-STRUCTURE OF THE RAR-GAMMA LIGAND-BINDING DOMAIN BOUND TO ALL-TRANS-RETINOIC ACID
    RENAUD, JP
    ROCHEL, N
    RUFF, M
    VIVAT, V
    CHAMBON, P
    GRONEMEYER, H
    MORAS, D
    [J]. NATURE, 1995, 378 (6558) : 681 - 689
  • [48] Nuclear hormone receptor coregulators in action: Diversity for shared tasks
    Robyr, D
    Wolffe, AP
    Wahli, W
    [J]. MOLECULAR ENDOCRINOLOGY, 2000, 14 (03) : 329 - 347
  • [49] Identification of TRACs (T-3 receptor-associating cofactors), a family of cofactors that associate with, and modulate the activity of, nuclear hormone receptors
    Sande, S
    Privalsky, ML
    [J]. MOLECULAR ENDOCRINOLOGY, 1996, 10 (07) : 813 - 825
  • [50] Two receptor interacting domains in the nuclear hormone receptor corepressor RIP13/N-CoR
    Seol, W
    Mahon, MJ
    Lee, YK
    Moore, DD
    [J]. MOLECULAR ENDOCRINOLOGY, 1996, 10 (12) : 1646 - 1655