Structure of the Anaphase-Promoting complex/cyclosome Interacting With a Mitotic Checkpoint Complex

Science. 2009 Mar 13;323(5920):1477-81. doi: 10.1126/science.1163300.

Abstract

Once all chromosomes are connected to the mitotic spindle (bioriented), anaphase is initiated by the protein ubiquitylation activity of the anaphase-promoting complex/cyclosome (APC/C) and its coactivator Cdc20 (APC/C(Cdc20)). Before chromosome biorientation, anaphase is delayed by a mitotic checkpoint complex (MCC) that inhibits APC/C(Cdc20). We used single-particle electron microscopy to obtain three-dimensional models of human APC/C in various functional states: bound to MCC, to Cdc20, or to neither (apo-APC/C). These experiments revealed that MCC associates with the Cdc20 binding site on APC/C, locks the otherwise flexible APC/C in a "closed" state, and prevents binding and ubiquitylation of a wide range of different APC/C substrates. These observations clarify the structural basis for the inhibition of APC/C by spindle checkpoint proteins.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anaphase
  • Anaphase-Promoting Complex-Cyclosome
  • Cdc20 Proteins
  • Cell Cycle Proteins / chemistry
  • Cell Cycle Proteins / metabolism
  • HeLa Cells
  • Humans
  • Image Processing, Computer-Assisted
  • Imaging, Three-Dimensional
  • Microscopy, Electron
  • Mitosis*
  • Models, Molecular
  • Protein Binding
  • Protein Conformation
  • Protein Structure, Tertiary
  • Spindle Apparatus / metabolism*
  • Ubiquitin-Conjugating Enzymes / chemistry
  • Ubiquitin-Conjugating Enzymes / metabolism
  • Ubiquitin-Protein Ligase Complexes / chemistry*
  • Ubiquitin-Protein Ligase Complexes / metabolism*
  • Ubiquitination

Substances

  • Cdc20 Proteins
  • Cell Cycle Proteins
  • CDC20 protein, human
  • UBE2C protein, human
  • Ubiquitin-Conjugating Enzymes
  • Ubiquitin-Protein Ligase Complexes
  • Anaphase-Promoting Complex-Cyclosome