Cyclin-dependent kinase 1-dependent activation of APC/C ubiquitin ligase.
Error-free genome duplication and segregation are ensured through the timely activation of ubiquitylation enzymes. The anaphase-promoting complex or cyclosome (APC/C), a multisubunit E3 ubiquitin ligase, is regulated by phosphorylation. However, the mechanism remains elusive. Using systematic reconstitution and analysis of vertebrate APC/Cs under physiological conditions, we show how cyclin-dependent kinase 1 (CDK1) activates the APC/C through coordinated phosphorylation between Apc3 and Apc1. Phosphorylation of the loop domains by CDK1 in complex with p9/Cks2 (a CDK regulatory subunit) controlled loading of coactivator Cdc20 onto APC/C. A phosphomimetic mutation introduced into Apc1 allowed Cdc20 to increase APC/C activity in interphase. These results define a previously unrecognized subunit-subunit communication over a distance and the functional consequences of CDK phosphorylation. Cdc20 is a potential therapeutic target, and our findings may facilitate the development of specific inhibitors.
Cell Cycle Control Group, UCL Cancer Institute, University College London, London WC1E 6DD, UK.
Kazuyuki
K
Fujimitsu
Cell Cycle Control Group, UCL Cancer Institute, University College London, London WC1E 6DD, UK.
Margaret
M
Grimaldi
Cell Cycle Control Group, UCL Cancer Institute, University College London, London WC1E 6DD, UK. h.yamano@ucl.ac.uk.
Hiroyuki
H
Yamano
D000705:Anaphase; D000818:Animals; D064189:Apc1 Subunit, Anaphase-Promoting Complex-Cyclosome / Q000235:genetics / Q000378:metabolism*; D064191:Apc3 Subunit, Anaphase-Promoting Complex-Cyclosome / Q000235:genetics / Q000378:metabolism*; D064199:Cdc20 Proteins / Q000378:metabolism; D064200:Cdh1 Proteins / Q000378:metabolism*; D004789:Enzyme Activation; D006801:Humans; D009154:Mutation; D010766:Phosphorylation; D014981:Xenopus
D064189:Apc1 Subunit, Anaphase-Promoting Complex-Cyclosome; D064191:Apc3 Subunit, Anaphase-Promoting Complex-Cyclosome; D064199:Cdc20 Proteins; D064200:Cdh1 Proteins