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

Wei Tian, Bing Li, Ross Warrington, Diana R. Tomchick, Hongtao Yu, Xuelian Luo

Research output: Contribution to journalArticle

54 Scopus citations

Abstract

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/CCdc20 is the target of the spindle checkpoint. Checkpoint inhibition of APC/CCdc20 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/CCdc20. Although both motifs contribute to securin ubiquitination by APC/CCdh1, 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.

Original languageEnglish (US)
Pages (from-to)18419-18424
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume109
Issue number45
DOIs
StatePublished - Nov 6 2012

Keywords

  • Crystallography
  • Mitosis
  • Molecular recognition
  • Multivalency

ASJC Scopus subject areas

  • General

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