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Structural basis for the interaction of TAK1 kinase with its activating protein TAB1

Kieron Brown1, Sarah C M Vial, Neesha Dedi

  • 1Vertex Pharmaceuticals (Europe) Ltd, 88 Milton Park, Abingdon, Oxfordshire OX14 4RY, UK.

Journal of Molecular Biology
|November 18, 2005
PubMed

Insights

Transforming growth factor-beta (TGF-beta)-activated kinase 1 (TAK1) requires TAK1-binding protein 1 (TAB1) for activation. Crystal structures reveal TAB1 binds TAK1 via a novel pocket, explaining their molecular interaction.

Area of Science:

  • Molecular Biology
  • Structural Biology
  • Biochemistry

Background:

  • Transforming growth factor-beta (TGF-beta)-activated kinase 1 (TAK1) is a MAPKKK family protein kinase.
  • TAK1 mediates intracellular signaling pathways activated by TGF-beta, interleukin-1, and tumor necrosis factor-alpha.
  • TAK1 requires TAK1-binding protein 1 (TAB1) for full activation, but the mechanism remains unclear.

Purpose of the Study:

  • To elucidate the molecular basis of TAK1 activation by TAB1.
  • To provide structural insights into the interaction between TAK1 and TAB1.

Main Methods:

  • Solved the crystal structure of a novel TAK1 chimeric protein.
  • Analyzed the structural basis of the TAK1-TAB1 interaction.

Main Results:

  • Identified a novel binding pocket on the TAK1 kinase domain.
  • Discovered a unique alpha-helix in the TAB1 binding domain.
  • Revealed an intimate hydrophobic association between TAK1 and TAB1, explaining the activation mechanism.

Conclusions:

  • The crystal structure provides a molecular explanation for TAB1-mediated TAK1 activation.
  • The findings highlight a specific hydrophobic interaction crucial for the protein activator-target relationship.

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