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Emi1 stably binds and inhibits the anaphase-promoting complex/cyclosome as a pseudosubstrate inhibitor

Julie J Miller1, Matthew K Summers, David V Hansen

  • 1Program in Molecular Pharmacology, Stanford University School of Medicine, Stanford, California 94305, USA.

Genes & Development
|August 22, 2006
PubMed

Insights

The anaphase-promoting complex/cyclosome (APC/C) inhibitor Emi1 directly binds APC/C, blocking substrate degradation. Emi1

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Biochemistry

Background:

  • Mitotic cyclin destruction, regulated by the anaphase-promoting complex/cyclosome (APC/C), is crucial for cell cycle progression.
  • The precise mechanism governing APC/C binding to its destruction box (D-box) substrates remains incompletely understood.

Purpose of the Study:

  • To elucidate the mechanism by which the APC/C inhibitor Emi1 regulates APC/C activity.
  • To investigate the structural basis of Emi1-APC/C interaction and its functional consequences.

Main Methods:

  • Biochemical assays to study protein-protein interactions.
  • Site-directed mutagenesis to analyze the function of Emi1 domains.
  • Analysis of APC/C-Emi1 complex formation.

Main Results:

  • Emi1 directly binds to the APC/C(Cdh1) complex, competing with D-box substrates for binding.
  • Emi1 possesses a D-box for APC/C binding and a zinc-binding region (ZBR) that inhibits APC/C ligase activity.
  • Mutation of the ZBR renders Emi1 a substrate of the APC/C, highlighting its role in regulating APC/C activity.

Conclusions:

  • Emi1 acts as a pseudosubstrate inhibitor of the APC/C, stabilizing cyclins by blocking substrate degradation.
  • The dual function of Emi1 (substrate binding and activity inhibition) provides a model for the evolution of E3 substrate inhibitors.

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