RRC ID 19689
著者 Chao WC, Kulkarni K, Zhang Z, Kong EH, Barford D.
タイトル Structure of the mitotic checkpoint complex.
ジャーナル Nature
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 p31(comet) (also known as MAD2L1-binding protein) compete for the same C-Mad2 interface, which explains how p31(comet) disrupts MCC assembly to antagonize the SAC. This study shows how APC/C inhibition is coupled to degron recognition by co-activators.
巻・号 484(7393)
ページ 208-13
公開日 2012-3-21
DOI 10.1038/nature10896
PII nature10896
PMID 22437499
MeSH Amino Acid Motifs Anaphase-Promoting Complex-Cyclosome Cdc20 Proteins Cdh1 Proteins Cell Cycle Proteins / chemistry* Cell Cycle Proteins / metabolism Conserved Sequence Crystallography, X-Ray Humans M Phase Cell Cycle Checkpoints* Mad2 Proteins Models, Molecular Multiprotein Complexes / chemistry* Multiprotein Complexes / metabolism Nuclear Proteins / chemistry* Nuclear Proteins / metabolism Protein Structure, Quaternary Protein Structure, Tertiary Saccharomyces cerevisiae Proteins / chemistry Saccharomyces cerevisiae Proteins / genetics Saccharomyces cerevisiae Proteins / metabolism Schizosaccharomyces / chemistry* Schizosaccharomyces pombe Proteins / chemistry* Schizosaccharomyces pombe Proteins / metabolism Spindle Apparatus Structure-Activity Relationship Substrate Specificity Ubiquitin-Protein Ligase Complexes / antagonists & inhibitors Ubiquitin-Protein Ligase Complexes / chemistry Ubiquitin-Protein Ligase Complexes / metabolism Ubiquitin-Protein Ligase Complexes / ultrastructure
IF 42.779
引用数 187
WOS 分野 CELL BIOLOGY
リソース情報
酵母 cDNA library (pTN-TH7)