The Mitotic Checkpoint Complex Requires an Evolutionary Conserved Cassette to Bind and Inhibit Active APC/C
Di Fiore B, Wurzenberger C, Davey NE & Pines J. (2016) Mol Cell. Nov 25. DOI: 10.1016/j.molcel.2016.11.006. [Epub ahead of print]
The authors are investigating the fine details of cell division (mitosis) in the stages leading up to anaphase, when replicated sister chromatids are pulled apart to opposite ends of the cell in order to give the correct complement of chromosomes to both of the daughter cells.
Working with a colleague in Dublin, they show that two newly identified ABBA motifs (sequences) in protein BubR1, part of the Mitotic Checkpoint Complex (MCC), are crucial because they mediate the binding of the Mitotic Checkpoint Complex (MCC) to inhibit the Anaphase Promoting Complex/ Cyclostome (APC/C). The inhibition occurs via the binding of Cdc20 to both ABBA motifs, where one Cdc20 is part of the MCC and the other part of the APC/C. These results help explain how the MCC distinguishes and preferentially binds active APC/C, which will happen when there is a need to inhibit the cell moving to anaphase.
The ABBA motifs are part of a longer sequence that is highly conserved throughout evolution, another pointer to the crucial role they play in regulating cell division.
The authors suggest that the ABBA motif may provide a target for small molecule inhibitors with the effect of disrupting mitosis, for example in rapidly-dividing cancer cells.
Abstract from the paper
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.
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