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

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

Authors

  • Miller JJ
  • Summers MK
  • Hansen DV
  • Nachury MV
  • Lehman NL
  • Loktev A
  • Jackson PK

Journal

Genes & development

Publication Data

September 1, 2006

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

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