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The SAC and the MCC

The SAC is active during mitosis and is composed of a set of conserved proteins, which prevent further mitotic progression until proper interactions between microtubules of the mitotic spindle and kinetochores on the sister chromatids have been achieved. Kinetochores are established on the centromere region of chromatids and are large protein structures able to bind to the dynamic plus ends of microtubules allowing chromosome alignment and segregation. It is believed that incorrectly attached kinetochores act as platforms for generating the inhibitory signal since removal of the last unattached kinetochore allows progression into anaphase. In support of this all checkpoint proteins and Cdc20 accumulate and turn over rapidly at unattached kinetochores.

 

Schematic of the role of the kinetochore in generating the inhibitory signal that inhibits Cdc20.

 

The exact role of kinetochores in generating an inhibitory signal is not clear, but the outcome is that Cdc20 is inhibited by the direct binding of Mad2 and BubR1-Bub3 to form what is referred to as the mitotic checkpoint complex (MCC). Within the MCC Mad2 and BubR1 are the proteins making a direct contact to Cdc20. Mad2 binds to a short consensus sequence in the N-terminus of Cdc20 and this allows for the binding of the BubR1-Bub3 complex, which appears to make a more extensive contact to Cdc20. The BubR1-Bub3 complex also appears to be the major kinetochore receptor for Cdc20. The exact stoichiometry of the MCC is still debated and indeed different forms of the MCC might exist. The MCC also exists as a larger complex in the form of a stable MCC-APC/C complex where Cdc20 appears positioned slightly differently on the APC/C as compared to its binding in the absence of checkpoint proteins. How exactly Cdc20 is inhibited when in the context of the MCC is not clear but since BubR1 contains a conserved KEN box motif essential for the checkpoint, which is a motif also found in APC/CCdc20 substrates, it might be that BubR1 acts as a pseudo-substrate and as a result blocks access of substrates.

 

Cryo-EM structure of the MCC (red) bound to the APC/C.

 

News

 

 

July 2016

Our PP2A-B56 motif paper

online in Molecular Cell

click here

 

July 2016

Our two pool BubR1 paper now

online at Nature Communications

click here

 

March 2016

Our Cdc20 phosphorylation paper

is now online at

Nature Communications

click here