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BS69/ZMYND11 C-Terminal Domains Bind and Inhibit EBNA2

Matthew R Harter1, Cheng-Der Liu2, Chih-Lung Shen2

  • 1Department of Biochemistry, University of California, Riverside, Riverside, California, United States of America.

Plos Pathogens
|February 5, 2016
PubMed

Insights

The tumor suppressor BS69 inhibits Epstein-Barr virus nuclear antigen 2 (EBNA2) by binding to its PXLXP motifs. This interaction blocks EBNA2-driven B cell immortalization, offering potential therapeutic strategies for EBV infection.

Area of Science:

  • Structural biology
  • Virology
  • Molecular oncology

Background:

  • Epstein-Barr virus (EBV) nuclear antigen 2 (EBNA2) is crucial for B cell immortalization by regulating viral and cellular gene expression.
  • The tumor suppressor BS69 (also known as ZMYND11) interacts with EBNA2, influencing EBV-driven processes.

Purpose of the Study:

  • To elucidate the structural basis of the interaction between the BS69 C-terminal region and EBNA2.
  • To investigate the functional consequences of this interaction on EBNA2-mediated transcription and B cell proliferation.

Main Methods:

  • X-ray crystallography to determine the structure of BS69CC-MYND in complex with an EBNA2 peptide.
  • Isothermal Titration Calorimetry (ITC) to analyze binding affinities.
  • Cell-based assays to assess EBNA2-mediated transcription activation and lymphoblastoid cell line (LCL) proliferation.

Main Results:

  • The coiled-coil domain of BS69 self-associates, enhancing the binding of its MYND domains to EBNA2.
  • BS69CC-MYND homodimers bind synergistically to two PXLXP motifs in EBNA2 (CR7 and CR8).
  • EBNA2 down-regulates BS69 expression in infected B cells. Ectopic BS69CC-MYND inhibits EBNA2-mediated transcription and LCL proliferation, with mutations in the MYND domain abolishing this effect.

Conclusions:

  • The C-terminal domains of BS69 act as a direct inhibitor of EBNA2.
  • The structural and functional characterization of the BS69-EBNA2 interaction provides insights into EBV pathogenesis.
  • This interaction represents a potential target for novel therapeutic strategies against EBV infection.

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