The Mitotic Checkpoint Complex Requires an Evolutionary Conserved Cassette to Bind and Inhibit Active APC/C
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Di Fiore, B., Wurzenberger, C., Davey, N., & Pines, J. (2016). The Mitotic Checkpoint Complex Requires an Evolutionary Conserved Cassette to Bind and Inhibit Active APC/C. Molecular Cell, 64 (6), 1144-1153. https://doi.org/10.1016/j.molcel.2016.11.006
The Spindle Assembly Checkpoint (SAC) ensures genomic stability by preventing sister chromatid separation until all chromosomes are attached to the spindle. It catalyzes the production of the Mitotic Checkpoint Complex (MCC), which inhibits Cdc20 to inactivate the Anaphase Promoting Complex/Cyclosome (APC/C). Here we show that two Cdc20-binding motifs in BubR1 of the recently identified ABBA motif class are crucial for the MCC to recognize active APC/C-Cdc20. Mutating these motifs eliminates MCC binding to the APC/C, thereby abolishing the SAC and preventing cells from arresting in response to microtubule poisons. These ABBA motifs flank a KEN box to form a cassette that is highly conserved through evolution, both in the arrangement and spacing of the ABBA-KEN-ABBA motifs, and association with the amino-terminal KEN box required to form the MCC. We propose that the ABBA-KEN-ABBA cassette holds the MCC onto the APC/C by binding the two Cdc20 molecules in the MCC-APC/C complex.
mitosis, checkpoint, Spindle Assembly Checkpoint, Anaphase Promoting Complex, Cyclosome, ABBA motif, BubR1, Cdc20
This work was supported by an SFI Starting Investigator Research Grant (13/SIRG/2193) to N.E.D. and a CR UK Programme grant C29/A13678 to J.P. J.P. acknowledges the financial support of Wellcome Trust Grant 092096 and CR UK Grant C6946/A14492 core support to the Gurdon Institute.
Wellcome Trust (092096/Z/10/Z)
Cancer Research UK (A14492)
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External DOI: https://doi.org/10.1016/j.molcel.2016.11.006
This record's URL: https://www.repository.cam.ac.uk/handle/1810/262048
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