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Structural basis for the antiproliferative activity of the Tob-hCaf1 complex

Masataka Horiuchi1, Kosei Takeuchi, Nobuo Noda

  • 1Department of Structural Biology, Graduate School of Pharmaceutical Sciences, Hokkaido University, Sapporo, Japan.

The Journal of Biological Chemistry
|March 12, 2009
PubMed

Insights

The Tob protein complex with human Caf1 (hCaf1) inhibits cell growth. Complex formation, not deadenylase activity, is key for Tob/hCaf1

Area of Science:

  • Molecular Biology
  • Structural Biology
  • Cell Biology

Background:

  • Tob/BTG proteins are antiproliferative factors.
  • They interact with CCR4-associated factor 1 (Caf1), a deadenylase component of the CCR4-Not complex.

Purpose of the Study:

  • Determine the crystal structure of the Tob N-terminal region complexed with human Caf1 (hCaf1).
  • Investigate the role of Caf1's deadenylase activity versus complex formation in Tob-mediated cell growth inhibition.

Main Methods:

  • X-ray crystallography to determine the structure of the Tob-hCaf1 complex.
  • Cell growth assays using wild-type and mutant proteins.

Main Results:

  • The crystal structure revealed a novel fold for Tob and similarity of hCaf1 to known catalytic domains.
  • hCaf1 association with Tob is mediated by both Box A and Box B regions.
  • Cell growth inhibition by Tob/hCaf1 depends on complex formation, not Caf1's deadenylase activity.

Conclusions:

  • Caf1 acts as a tether, bringing Tob to the CCR4-Not complex.
  • Tob, via its C-terminal region, recruits factors like poly(A)-binding proteins to inhibit cell proliferation.

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