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Structural and Functional Impacts of ER Coactivator Sequential Recruitment

Ping Yi1, Zhao Wang2, Qin Feng1

  • 1Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA.

Molecular Cell
|August 29, 2017
PubMed

Insights

Estrogen receptor (ER) transcription involves sequential coactivator recruitment. Late-recruited CARM1 structurally reorganizes the complex, enhancing ER activity through crosstalk with early coactivators like SRC-3 and p300.

Area of Science:

  • Molecular Biology
  • Structural Biology
  • Epigenetics

Background:

  • Nuclear receptors orchestrate gene transcription through the sequential recruitment of coactivator proteins.
  • Estrogen receptor (ER) utilizes a cascade of coactivators, including SRC-3, p300/CBP, and CARM1, with distinct temporal dependencies.

Purpose of the Study:

  • To elucidate the structural and functional interplay between sequentially recruited coactivators in estrogen receptor-mediated transcription.
  • To investigate the role of CARM1's delayed recruitment in modulating the ER-coactivator complex.

Main Methods:

  • Cryo-electron microscopy (cryo-EM) for structural analysis of the ER-coactivator complex.
  • Biochemical assays to assess coactivator activities and interactions.
  • Histone modification analysis (HAT and methylation) to evaluate functional outcomes.

Main Results:

  • CARM1 recruitment to the ER complex is temporally delayed compared to SRC-3 and p300.
  • CARM1 interacts with and induces conformational changes in p300, enhancing its HAT activity on histone H3K18.
  • This p300 activation promotes CARM1's methyltransferase activity on histone H3R17, amplifying transcriptional output.

Conclusions:

  • Sequential coactivator recruitment is critical for ER transcriptional regulation, involving structural crosstalk between early and late factors.
  • CARM1's delayed recruitment and its impact on p300 activity reveal a novel mechanism for fine-tuning gene expression.
Keywords:
CARM1SRC-3coactivatorcryo-EM structureestrogen receptorhistone modificationp300sequential recruitment

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