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Autoinhibition of the HECT-type ubiquitin ligase Smurf2 through its C2 domain

Silke Wiesner1, Abiodun A Ogunjimi, Hong-Rui Wang

  • 1Hospital for Sick Children, 555 University Avenue, Toronto, Ontario M5G 1X8, Canada. silke@pound.med.utoronto.ca

Cell
|August 28, 2007
PubMed

Insights

Protein ubiquitination regulates cellular processes. The Smurf2 E3 ligase

Area of Science:

  • Molecular Biology
  • Biochemistry
  • Cellular Biology

Background:

  • Protein ubiquitination is a key post-translational modification controlling diverse cellular functions.
  • Ubiquitin ligases (E3s) mediate substrate ubiquitination, often targeting themselves and substrates for degradation.
  • Mechanisms governing E3 ligase catalytic activity remain largely unelucidated.

Purpose of the Study:

  • To investigate the regulatory mechanisms of C2-WW-HECT-domain E3 ligases, focusing on Smurf2.
  • To elucidate how Smurf2's catalytic activity is controlled to prevent uncontrolled degradation of substrates and itself.

Main Methods:

  • Biochemical assays to study Smurf2 activity and interactions.
  • Nuclear Magnetic Resonance (NMR) spectroscopy to analyze domain interactions.
  • Cellular studies to assess Smurf2 stability and function in vivo.

Main Results:

  • An intramolecular interaction between the C2 and HECT domains of Smurf2 inhibits its ligase activity.
  • This C2-HECT interaction stabilizes Smurf2 protein levels within cells.
  • NMR analysis revealed the C2 domain binds near the catalytic cysteine, hindering ubiquitin thioester formation.
  • Smad7 binding antagonizes the inhibitory C2-HECT interaction, activating Smurf2.

Conclusions:

  • Autoinhibition via C2-HECT domain interaction is a mechanism regulating a subset of HECT-type E3 ligases.
  • This autoinhibitory mechanism protects E3 ligases and their substrates from premature or futile degradation.
  • Understanding this regulation provides insights into controlling TGF-beta signaling and other pathways mediated by Smurf2.

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