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Regulation of Smurf2 ubiquitin ligase activity by anchoring the E2 to the HECT domain.

The conjugation of ubiquitin to proteins involves a cascade of activating (E1), conjugating (E2), and ubiquitin-ligating (E3) type enzymes that commonly signal protein destruction. In TGFbeta signaling the inhibitory protein Smad7 recruits Smurf2, an E3 of the C2-WW-HECT domain class, to the TGFbeta receptor complex to facilitate receptor degradation. Here, we demonstrate that the amino-terminal domain (NTD) of Smad7 stimulates Smurf activity by recruiting the E2, UbcH7, to the HECT domain. A 2.1 A resolution X-ray crystal structure of the Smurf2 HECT domain reveals that it has a suboptimal E2 binding pocket that could be optimized by mutagenesis to generate a HECT domain that functions independently of Smad7 and potently inhibits TGFbeta signaling. Thus, E2 enzyme recognition by an E3 HECT enzyme is not constitutively competent and provides a point of control for regulating the ubiquitin ligase activity through the action of auxiliary proteins.

Pubmed ID: 16061177

Authors

  • Ogunjimi AA
  • Briant DJ
  • Pece-Barbara N
  • Le Roy C
  • Di Guglielmo GM
  • Kavsak P
  • Rasmussen RK
  • Seet BT
  • Sicheri F
  • Wrana JL

Journal

Molecular cell

Publication Data

August 5, 2005

Associated Grants

None

Mesh Terms

  • Amino Acid Motifs
  • Amino Acid Sequence
  • Binding Sites
  • Catalysis
  • Cell Line
  • Crystallography, X-Ray
  • DNA-Binding Proteins
  • Enzyme Activation
  • Humans
  • Models, Molecular
  • Molecular Sequence Data
  • Mutagenesis, Site-Directed
  • Mutation
  • Peptide Fragments
  • Protein Binding
  • Protein Structure, Tertiary
  • Receptors, Transforming Growth Factor beta
  • Recombinant Proteins
  • Sequence Homology, Amino Acid
  • Signal Transduction
  • Smad7 Protein
  • Trans-Activators
  • Transfection
  • Ubiquitin
  • Ubiquitin-Activating Enzymes
  • Ubiquitin-Conjugating Enzymes
  • Ubiquitin-Protein Ligases