The hinge region of the human estrogen receptor determines functional synergy between AF-1 and AF-2 in the quantitative response to estradiol and tamoxifen

J Cell Sci. 2010 Apr 15;123(Pt 8):1253-61. doi: 10.1242/jcs.061135. Epub 2010 Mar 23.


Human estrogen receptors alpha and beta (ERalpha and ERbeta) greatly differ in their target genes, transcriptional potency and cofactor-binding capacity, and are differentially expressed in various tissues. In classical estrogen response element (ERE)-mediated transactivation, ERbeta has a markedly reduced activation potential compared with ERalpha; the mechanism underlying this difference is unclear. Here, we report that the binding of steroid receptor coactivator-1 (SRC-1) to the AF-1 domain of ERalpha is essential but not sufficient to facilitate synergy between the AF-1 and AF-2 domains, which is required for a full agonistic response to estradiol (E2). Complete synergy is achieved through the distinct hinge domain of ERalpha, which enables combined action of the AF-1 and AF-2 domains. AF-1 of ERbeta lacks the capacity to interact with SRC-1, which prevents hinge-mediated synergy between AF-1 and AF-2, thereby explaining the reduced E2-mediated transactivation of ERbeta. Transactivation of ERbeta by E2 requires only the AF-2 domain. A weak agonistic response to tamoxifen occurs for ERalpha, but not for ERbeta, and depends on AF-1 and the hinge-region domain of ERalpha.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Line, Tumor
  • Cyclic AMP-Dependent Protein Kinases / metabolism
  • Estradiol / pharmacology*
  • Estrogen Receptor alpha / chemistry*
  • Estrogen Receptor alpha / metabolism*
  • Estrogen Receptor beta / chemistry
  • Estrogen Receptor beta / metabolism
  • Humans
  • Mutant Proteins / chemistry
  • Mutant Proteins / metabolism
  • Nuclear Receptor Coactivator 1 / metabolism
  • Protein Binding / drug effects
  • Protein Conformation
  • Protein Structure, Tertiary
  • Protein Transport / drug effects
  • RNA Polymerase II / metabolism
  • Structure-Activity Relationship
  • Tamoxifen / pharmacology*
  • Transcriptional Activation / drug effects
  • Transcriptional Activation / genetics


  • ESR1 protein, human
  • Estrogen Receptor alpha
  • Estrogen Receptor beta
  • Mutant Proteins
  • Tamoxifen
  • Estradiol
  • NCOA1 protein, human
  • Nuclear Receptor Coactivator 1
  • Cyclic AMP-Dependent Protein Kinases
  • RNA Polymerase II