Figure 5.
Figure 5. Hypothetical organization of the MCC with two Cdc20 protomers. (A) The MCC might be assembled from two subcomplexes, Mad2–Cdc20 and BubR1/Mad3–Bub3–Cdc20 (Bub3 is not shown to improve clarity). Each of these potential inhibitors of the APC/C might be generated with different rates and mechanisms at the kinetochore, only afterward becoming assembled into one complex. (B) Two hypothetical complexes resulting from the encounter of the Mad2–Cdc20 and BubR1/Mad3–Cdc20 subcomplexes. (left) Cdc20 bound to Mad2 (Cdc20-2) binds BubR1 through the KEN2 motif. The direct interaction of Cdc20 with KEN2 is probably low affinity, but complex formation is driven by cooperativity: BubR1 is in contact with both Mad2 and Cdc20, which in turn interact via the MIM. Cdc20-1 bound at the KEN1 motif is in principle available for APC/C binding via its N-terminal (N) tail. (right) The core of this alternative configuration is similar to that of the crystallized MCC. In this alternative configuration, Cdc20-2 binds to KEN2. In the absence of additional hypothetical contacts, this configuration is less likely because KEN2 is not required for the interaction of BubR1/Mad3 with Cdc20, suggesting that its direct contribution to the overall binding affinity of the interaction is modest. (C) In solution, p31comet may promote the release of a Cdc20–Mad2 complex from BubR1/Mad3–Cdc20 by direct competition with BubR1/Mad3 for Mad2 binding. In turn, BubR1/Mad3–Cdc20 might dissociate via additional mechanisms (e.g., phosphorylation, dephosphorylation, and ATP-dependent processes). (D) One of the two MCC configurations shown in B bound to the APC/C. (E) p31comet might detach Mad2 from its interaction with BubR1/Mad3, initially without disrupting MCC, which is stabilized by additional interactions with the APC/C. Cdc20-2, which is bound to Mad2-p31comet, is directed to the catalytic machinery of the APC/C for ubiquitination. This reaction requires Mnd2/Apc15 and ultimately results in the destruction of Cdc20-2. (F) A BubR1/Mad3–Cdc20-1 complex is left behind. This complex can be removed from the APC/C through similar mechanisms to those discussed in C.

Hypothetical organization of the MCC with two Cdc20 protomers. (A) The MCC might be assembled from two subcomplexes, Mad2–Cdc20 and BubR1/Mad3–Bub3–Cdc20 (Bub3 is not shown to improve clarity). Each of these potential inhibitors of the APC/C might be generated with different rates and mechanisms at the kinetochore, only afterward becoming assembled into one complex. (B) Two hypothetical complexes resulting from the encounter of the Mad2–Cdc20 and BubR1/Mad3–Cdc20 subcomplexes. (left) Cdc20 bound to Mad2 (Cdc20-2) binds BubR1 through the KEN2 motif. The direct interaction of Cdc20 with KEN2 is probably low affinity, but complex formation is driven by cooperativity: BubR1 is in contact with both Mad2 and Cdc20, which in turn interact via the MIM. Cdc20-1 bound at the KEN1 motif is in principle available for APC/C binding via its N-terminal (N) tail. (right) The core of this alternative configuration is similar to that of the crystallized MCC. In this alternative configuration, Cdc20-2 binds to KEN2. In the absence of additional hypothetical contacts, this configuration is less likely because KEN2 is not required for the interaction of BubR1/Mad3 with Cdc20, suggesting that its direct contribution to the overall binding affinity of the interaction is modest. (C) In solution, p31comet may promote the release of a Cdc20–Mad2 complex from BubR1/Mad3–Cdc20 by direct competition with BubR1/Mad3 for Mad2 binding. In turn, BubR1/Mad3–Cdc20 might dissociate via additional mechanisms (e.g., phosphorylation, dephosphorylation, and ATP-dependent processes). (D) One of the two MCC configurations shown in B bound to the APC/C. (E) p31comet might detach Mad2 from its interaction with BubR1/Mad3, initially without disrupting MCC, which is stabilized by additional interactions with the APC/C. Cdc20-2, which is bound to Mad2-p31comet, is directed to the catalytic machinery of the APC/C for ubiquitination. This reaction requires Mnd2/Apc15 and ultimately results in the destruction of Cdc20-2. (F) A BubR1/Mad3–Cdc20-1 complex is left behind. This complex can be removed from the APC/C through similar mechanisms to those discussed in C.

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