Structure of a biologically active estrogen receptor-coactivator complex on DNA

Mol Cell. 2015 Mar 19;57(6):1047-1058. doi: 10.1016/j.molcel.2015.01.025. Epub 2015 Feb 26.

Abstract

Estrogen receptor (ER/ESR1) is a transcription factor critical for development, reproduction, metabolism, and cancer. ER function hinges on its ability to recruit primary and secondary coactivators, yet structural information on the full-length receptor-coactivator complex to complement preexisting and sometimes controversial biochemical information is lacking. Here, we use cryoelectron microscopy (cryo-EM) to determine the quaternary structure of an active complex of DNA-bound ERα, steroid receptor coactivator 3 (SRC-3/NCOA3), and a secondary coactivator (p300/EP300). Our structural model suggests the following assembly mechanism for the complex: each of the two ligand-bound ERα monomers independently recruits one SRC-3 protein via the transactivation domain of ERα; the two SRC-3s in turn bind to different regions of one p300 protein through multiple contacts. We also present structural evidence for the location of activation function 1 (AF-1) in a full-length nuclear receptor, which supports a role for AF-1 in SRC-3 recruitment.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Binding Sites
  • Cryoelectron Microscopy
  • DNA / chemistry
  • DNA / metabolism
  • E1A-Associated p300 Protein / chemistry*
  • E1A-Associated p300 Protein / metabolism
  • Estrogen Receptor alpha / chemistry*
  • Estrogen Receptor alpha / metabolism
  • Histone Acetyltransferases / metabolism
  • Humans
  • Multiprotein Complexes / chemistry
  • Multiprotein Complexes / metabolism
  • Nuclear Receptor Coactivator 3 / chemistry*
  • Nuclear Receptor Coactivator 3 / metabolism
  • Protein Conformation
  • Protein Structure, Tertiary
  • Response Elements

Substances

  • Estrogen Receptor alpha
  • Multiprotein Complexes
  • estrogen receptor alpha, human
  • DNA
  • E1A-Associated p300 Protein
  • EP300 protein, human
  • Histone Acetyltransferases
  • NCOA3 protein, human
  • Nuclear Receptor Coactivator 3

Associated data

  • GEO/GSM1010800