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Structural Insights into BET Client Recognition of Endometrial and Prostate Cancer-Associated SPOP Mutants

Michael Sebastian Ostertag1, Wiebke Hutwelker2, Oliver Plettenburg2

  • 1Institute of Structural Biology, Helmholtz Zentrum München, Ingolstädter Landstr. 1, 85764 Neuherberg, Germany; Center for Integrated Protein Science Munich at Chair of Biomolecular NMR Spectroscopy, Department Chemie, Technische Universität München, Lichtenbergstrasse 4, 85747 Garching, Germany.

Journal of Molecular Biology
|April 27, 2019
PubMed

Insights

SPOP mutations in cancer impact BET protein levels differently, affecting drug response. Structural studies reveal mechanisms for prostate cancer, but endometrial cancer suggests a more complex SPOP regulation in BET protein therapy.

Area of Science:

  • Oncology
  • Structural Biology
  • Molecular Mechanisms

Background:

  • BET proteins (e.g., BRD3) are oncogenic transcriptional coactivators.
  • SPOP binding promotes proteasomal degradation of BET proteins.
  • SPOP mutations in endometrial and prostate cancers influence drug susceptibility differently.

Purpose of the Study:

  • To elucidate the structural and mechanistic basis of SPOP mutations in cancer.
  • To investigate the impact of SPOP mutations on BET protein levels and drug susceptibility.
  • To provide insights for personalized medicine approaches in cancer therapy.

Main Methods:

  • Co-crystal structure determination of SPOP and BRD3.
  • Biophysical analyses of SPOP-BRD3 interactions.
  • Assessment of SPOP mutant binding behavior.

Main Results:

  • The first co-crystal structure of SPOP and BRD3 was determined.
  • Prostate cancer-associated SPOP mutants exhibit loss-of-function, increasing BET levels.
  • Endometrial cancer-associated SPOP mutants show no altered binding, suggesting complex regulation.

Conclusions:

  • Structural and biophysical data explain SPOP's role in prostate cancer drug resistance.
  • Endometrial cancer SPOP mutations indicate a regulatory mechanism beyond direct binding alteration.
  • SPOP mutation screening can inform personalized BET inhibitor therapy for cancer treatment.
Keywords:
BET proteinSPOPcancerubiquitinationx-ray crystallograpgy

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