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

Genes & development | Sep 1, 2006

http://www.ncbi.nlm.nih.gov/pubmed/16921029

The periodic destruction of mitotic cyclins is triggered by the activation of the anaphase-promoting complex/cyclosome (APC/C) in mitosis. Although the ability of the APC/C to recognize destruction box (D-box) substrates oscillates throughout the cell cycle, the mechanism regulating APC/C binding to D-box substrates remains unclear. Here, we show that the APC/C inhibitor Emi1 tightly binds both the APC/C and its Cdh1 activator, binds to the D-box receptor site on the APC/C(Cdh1), and competes with APC/C substrates for D-box binding. Emi1 itself contains a conserved C-terminal D-box, which provides APC/C-binding affinity, and a conserved zinc-binding region (ZBR), which antagonizes APC/C E3 ligase activity independent of tight APC binding. Mutation of the ZBR converts Emi1 into a D-box-dependent APC/C substrate. The identification of a direct Emi1-APC/C complex further explains how Emi1 functions as a stabilizing factor for cyclin accumulation and the need to destroy Emi1 for APC/C activation in mitosis. The combination of a degron/E3 recognition site and an anti-ligase function in Emi1 suggests a general model for how E3 substrates evolve to become pseudosubstrate inhibitors.

Pubmed ID: 16921029 RIS Download

Mesh terms: Amino Acid Motifs | Anaphase-Promoting Complex-Cyclosome | Binding, Competitive | Cadherins | Cell Cycle Proteins | Cell Nucleus | Conserved Sequence | Enzyme Inhibitors | F-Box Proteins | HeLa Cells | Humans | Interphase | Protein Binding | Substrate Specificity | Ubiquitin-Protein Ligase Complexes

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Associated grants

  • Agency: NCI NIH HHS, Id: CA09151
  • Agency: NIGMS NIH HHS, Id: GM07365
  • Agency: NIGMS NIH HHS, Id: R01 GM54811
  • Agency: NIGMS NIH HHS, Id: R01 GM60439
  • Agency: NCI NIH HHS, Id: T32 CA009151

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