title: Mad2 and the APC/C compete for the same site on Cdc20 to ensure proper chromosome segregation.
abstract: The spindle assembly checkpoint (SAC) is essential to ensure proper chromosome segregation and thereby maintain genomic stability. The SAC monitors chromosome attachment, and any unattached chromosomes generate a "wait anaphase" signal that blocks chromosome segregation. The target of the SAC is Cdc20, which activates the anaphase-promoting complex/cyclosome (APC/C) that triggers anaphase and mitotic exit by ubiquitylating securin and cyclin B1. The inhibitory complex formed by the SAC has recently been shown to inhibit Cdc20 by acting as a pseudosubstrate inhibitor, but in this paper, we show that Mad2 also inhibits Cdc20 by binding directly to a site required to bind the APC/C. Mad2 and the APC/C competed for Cdc20 in vitro, and a Cdc20 mutant that does not bind stably to Mad2 abrogated the SAC in vivo. Thus, we provide insights into how Cdc20 binds the APC/C and uncover a second mechanism by which the SAC inhibits the APC/C.
authors.affiliation: The Gurdon Institute, University of Cambridge, Cambridge CB2 1QN, England, UK.
authors.forename: Daisuke
authors.initials: D
authors.lastname: Izawa
authors.forename: Jonathon
authors.initials: J
authors.lastname: Pines
mesh_terms: D064173:Anaphase-Promoting Complex-Cyclosome; D001665:Binding Sites; D002135:Calcium-Binding Proteins / Q000378:metabolism*; D064199:Cdc20 Proteins; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D020090:Chromosome Segregation / Q000235:genetics; D006801:Humans; D059566:M Phase Cell Cycle Checkpoints / Q000235:genetics; D064246:Mad2 Proteins; D012097:Repressor Proteins / Q000378:metabolism*; D043743:Ubiquitin-Protein Ligase Complexes / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: D002135:Calcium-Binding Proteins; D064199:Cdc20 Proteins; D018797:Cell Cycle Proteins; C577697:MAD2L1 protein, human; D064246:Mad2 Proteins; D012097:Repressor Proteins; C577488:CDC20 protein, human; D043743:Ubiquitin-Protein Ligase Complexes; D064173:Anaphase-Promoting Complex-Cyclosome