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Structural analysis of human Cdc20 supports multisite degron recognition by APC/C.

The anaphase-promoting complex/cyclosome (APC/C) promotes anaphase onset and mitotic exit through ubiquitinating securin and cyclin B1. The mitotic APC/C activator, the cell division cycle 20 (Cdc20) protein, directly interacts with APC/C degrons--the destruction (D) and KEN boxes. APC/C(Cdc20) is the target of the spindle checkpoint. Checkpoint inhibition of APC/C(Cdc20) requires the binding of a BubR1 KEN box to Cdc20. How APC/C recognizes substrates is not understood. We report the crystal structures of human Cdc20 alone or bound to a BubR1 KEN box. Cdc20 has a disordered N-terminal region and a C-terminal WD40 β propeller with a preformed KEN-box-binding site at its top face. We identify a second conserved surface at the side of the Cdc20 β propeller as a D-box-binding site. The D box of securin, but not its KEN box, is critical for securin ubiquitination by APC/C(Cdc20). Although both motifs contribute to securin ubiquitination by APC/C(Cdh1), securin mutants lacking either motif are efficiently ubiquitinated. Furthermore, D-box peptides diminish the ubiquitination of KEN-box substrates by APC/C(Cdh1), suggesting possible competition between the two motifs. Our results indicate the lack of strong positive cooperativity between the two degrons of securin. We propose that low-cooperativity, multisite target recognition enables APC/C to robustly ubiquitinate diverse substrates and helps to drive cell cycle oscillations.

Pubmed ID: 23091007

Authors

  • Tian W
  • Li B
  • Warrington R
  • Tomchick DR
  • Yu H
  • Luo X

Journal

Proceedings of the National Academy of Sciences of the United States of America

Publication Data

November 6, 2012

Associated Grants

  • Agency: NIGMS NIH HHS, Id: GM085004
  • Agency: Howard Hughes Medical Institute, Id:

Mesh Terms

  • Anaphase-Promoting Complex-Cyclosome
  • Binding Sites
  • Carrier Proteins
  • Cdc20 Proteins
  • Cell Cycle Proteins
  • Conserved Sequence
  • Humans
  • Models, Molecular
  • Mutagenesis
  • Protein Binding
  • Protein Structure, Tertiary
  • Protein-Serine-Threonine Kinases
  • Proteolysis
  • Substrate Specificity
  • Ubiquitin-Protein Ligase Complexes
  • Ubiquitination