CARD-mediated autoinhibition of cIAP1's E3 ligase activity suppresses cell proliferation and migration

Mol Cell. 2011 Jun 10;42(5):569-83. doi: 10.1016/j.molcel.2011.04.008. Epub 2011 May 5.

Abstract

E3 ligases mediate the covalent attachment of ubiquitin to target proteins thereby enabling ubiquitin-dependent signaling. Unraveling how E3 ligases are regulated is important because miscontrolled ubiquitylation can lead to disease. Cellular inhibitor of apoptosis (cIAP) proteins are E3 ligases that modulate diverse biological processes such as cell survival, proliferation, and migration. Here, we have solved the structure of the caspase recruitment domain (CARD) of cIAP1 and identified that it is required for cIAP1 autoregulation. We demonstrate that the CARD inhibits activation of cIAP1's E3 activity by preventing RING dimerization, E2 binding, and E2 activation. Moreover, we show that the CARD is required to suppress cell proliferation and migration. Further, CARD-mediated autoregulation is also necessary to maximally suppress caspase-8-dependent apoptosis and vascular tree degeneration in vivo. Taken together, our data reveal mechanisms by which the E3 ligase activity of cIAP1 is controlled, and how its deregulation impacts on cell proliferation, migration and cell survival.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Cell Movement
  • Cell Proliferation
  • Cell Survival
  • Humans
  • Inhibitor of Apoptosis Proteins / chemistry
  • Inhibitor of Apoptosis Proteins / genetics
  • Inhibitor of Apoptosis Proteins / physiology*
  • Molecular Sequence Data
  • Nuclear Magnetic Resonance, Biomolecular
  • Protein Structure, Tertiary / physiology
  • Sequence Alignment
  • Static Electricity
  • Ubiquitin-Protein Ligases / chemistry
  • Ubiquitin-Protein Ligases / physiology*
  • Zebrafish / genetics
  • Zebrafish / metabolism

Substances

  • Inhibitor of Apoptosis Proteins
  • Ubiquitin-Protein Ligases

Associated data

  • PDB/UNKNOWN