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Chemical Inactivation of the E3 Ubiquitin Ligase Cereblon by Pomalidomide-based Homo-PROTACs
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Chemical Inactivation of the E3 Ubiquitin Ligase Cereblon by Pomalidomide-based Homo-PROTACs

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Smac mimetics activate the E3 ligase activity of cIAP1 protein by promoting RING domain dimerization

Rebecca Feltham1, Bodhi Bettjeman, Rhesa Budhidarmo

  • 1Department of Biochemistry, La Trobe University, Victoria 3086, Australia.

The Journal of Biological Chemistry
|March 12, 2011
PubMed

Insights

Smac mimetics activate inhibitor of apoptosis (IAP) E3 ligases by promoting RING domain dimerization. This mechanism explains how Smac mimetics induce cIAP1 destruction and offers insights into IAP activation.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Oncology

Background:

  • Inhibitor of apoptosis (IAP) proteins are crucial ubiquitin E3 ligases regulating cell survival and cancer.
  • IAP antagonists (Smac mimetics) induce autoubiquitylation, but the underlying mechanism remains unclear.

Purpose of the Study:

  • To elucidate the mechanism by which Smac mimetics activate cIAP1 and cIAP2 E3 ligase activity.
  • To investigate the role of RING domain dimerization and BIR domains in IAP regulation.

Main Methods:

  • Utilized monomeric RING mutants to assess E3 ligase activity and E2 enzyme interaction.
  • Investigated the effect of Smac mimetics on cIAP1 and cIAP2 dimerization and autoubiquitylation.
  • Compared the activity and Smac mimetic response of cIAP1 and cIAP2.

Main Results:

  • RING dimerization is essential for cIAP1 and cIAP2 E3 ligase activity.
  • cIAP1's BIR domains inhibit RING dimerization, maintaining it as an inactive monomer.
  • Smac mimetics relieve BIR-mediated inhibition, enabling cIAP1 RING dimerization and activation.
  • cIAP2 exhibits a more stable dimer with higher intrinsic activity, showing less activation by Smac mimetics.

Conclusions:

  • Smac mimetics activate cIAP1 by promoting RING dimerization, explaining its rapid destruction.
  • The findings provide a mechanistic basis for Smac mimetic action and suggest pathways for cIAP1 activation.

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