Structure of the mitotic checkpoint complex
- 21 March 2012
- journal article
- research article
- Published by Springer Science and Business Media LLC in Nature
- Vol. 484 (7393), 208-213
- https://doi.org/10.1038/nature10896
Abstract
In mitosis, the spindle assembly checkpoint (SAC) ensures genome stability by delaying chromosome segregation until all sister chromatids have achieved bipolar attachment to the mitotic spindle. The SAC is imposed by the mitotic checkpoint complex (MCC), whose assembly is catalysed by unattached chromosomes and which binds and inhibits the anaphase-promoting complex/cyclosome (APC/C), the E3 ubiquitin ligase that initiates chromosome segregation. Here, using the crystal structure of Schizosaccharomyces pombe MCC (a complex of mitotic spindle assembly checkpoint proteins Mad2, Mad3 and APC/C co-activator protein Cdc20), we reveal the molecular basis of MCC-mediated APC/C inhibition and the regulation of MCC assembly. The MCC inhibits the APC/C by obstructing degron recognition sites on Cdc20 (the substrate recruitment subunit of the APC/C) and displacing Cdc20 to disrupt formation of a bipartite D-box receptor with the APC/C subunit Apc10. Mad2, in the closed conformation (C-Mad2), stabilizes the complex by optimally positioning the Mad3 KEN-box degron to bind Cdc20. Mad3 and p31comet (also known as MAD2L1-binding protein) compete for the same C-Mad2 interface, which explains how p31comet disrupts MCC assembly to antagonize the SAC. This study shows how APC/C inhibition is coupled to degron recognition by co-activators.Keywords
This publication has 61 references indexed in Scilit:
- Mutual regulation between the spindle checkpoint and APC/CSeminars in Cell & Developmental Biology, 2011
- Structures of APC/CCdh1 with substrates identify Cdh1 and Apc10 as the D-box co-receptorNature, 2010
- Unattached Kinetochores Catalyze Production of an Anaphase Inhibitor that Requires a Mad2 Template to Prime Cdc20 for BubR1 BindingDevelopmental Cell, 2009
- BubR1 N Terminus Acts as a Soluble Inhibitor of Cyclin B Degradation by APC/CCdc20 in InterphaseDevelopmental Cell, 2009
- Protein Metamorphosis: The Two-State Behavior of Mad2Structure, 2008
- The Mad2 Conformational Dimer: Structure and Implications for the Spindle Assembly CheckpointCell, 2007
- p31comet Blocks Mad2 Activation through Structural MimicryCell, 2007
- The Mad1/Mad2 Complex as a Template for Mad2 Activation in the Spindle Assembly CheckpointCurrent Biology, 2005
- Feedback control of mitosis in budding yeastCell, 1991
- S. cerevisiae genes required for cell cycle arrest in response to loss of microtubule functionCell, 1991