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A structural basis for the assembly and functions of a viral polymer that inactivates multiple tumor suppressors

Horng D Ou1, Witek Kwiatkowski, Thomas J Deerinck

  • 1Molecular and Cell Biology Laboratory, Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, CA 92037, USA.

Cell
|October 16, 2012
PubMed

Insights

Adenovirus oncoprotein E4-ORF3 forms a nuclear polymer by assembling dimers. This viral protein matrix traps multiple tumor suppressors, revealing a novel mechanism for oncogenesis.

Area of Science:

  • Molecular Biology
  • Virology
  • Structural Biology

Background:

  • DNA tumor viruses utilize small oncoproteins to disrupt cellular functions.
  • The structural mechanisms behind adenovirus oncoproteins' diverse roles are not well understood.
  • Adenovirus E4-ORF3 protein is known to inactivate key tumor suppressors like p53 and PML.

Purpose of the Study:

  • To elucidate the structural basis for the multifunctional nature of adenovirus E4-ORF3.
  • To understand how E4-ORF3 forms polymers and interacts with cellular targets.
  • To investigate the assembly mechanism and quaternary structure of E4-ORF3.

Main Methods:

  • Identification and characterization of E4-ORF3 oligomerization mutants.
  • X-ray crystallography to determine the structure of E4-ORF3.
  • Analysis of E4-ORF3 polymer formation and interactions with tumor suppressors.

Main Results:

  • E4-ORF3 forms a dimer with a unique β-core structure.
  • Dimer units assemble into linear and branched chains via C-terminal tail exchanges, forming a nuclear polymer network.
  • The E4-ORF3 polymer network exhibits avidity-driven interactions with PML and creates a novel binding interface for the MRN complex.

Conclusions:

  • Adenovirus E4-ORF3 employs a small protein structure to form a multivalent matrix, trapping multiple tumor suppressors.
  • This oligomerization strategy allows E4-ORF3 to efficiently disrupt cellular pathways critical for tumor suppression.
  • The findings provide insights into viral oncogenesis and potential therapeutic targets.

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