The ubiquitin ligase Anaphase-Promoting Complex/Cyclosome (APC/C) and its regulatory protein Cdc20 play important roles in the control of different stages of mitosis. APC/C associated with Cdc20 is active and promotes metaphase–anaphase transition by targeting for degradation inhibitors of anaphase initiation. Earlier in mitosis, premature action of APC/C is prevented by the mitotic checkpoint (or spindle assembly checkpoint) system, which ensures that anaphase is not initiated until all chromosomes are properly attached to the mitotic spindle. The active mitotic checkpoint system promotes the assembly of a Mitotic Checkpoint Complex (MCC), which binds to APC/C and inhibits its activity. The interaction of MCC with APC/C is strongly enhanced by Cdc20 bound to APC/C. While the association of Cdc20 with APC/C was known to be essential for both these stages of mitosis, it was not known how Cdc20 remains bound in spite of ongoing processes, phosphorylation and ubiquitylation, that stimulate its release from APC/C. We find that MCC strongly inhibits the release of Cdc20 from APC/C by the action of mitotic protein kinase Cdk1-cyclin B. This is not due to protection from phosphorylation of specific sites in Cdc20 that affect its interaction with APC/C. Rather, MCC stabilizes the binding to APC/C of partially phosphorylated forms of Cdc20. MCC also inhibits the autoubiquitylation of APC/C-bound Cdc20 and its ubiquitylation-promoted release from APC/C. We propose that these actions of MCC to maintain Cdc20 bound to APC/C in mitosis are essential for the control of mitosis during active mitotic checkpoint and in subsequent anaphase initiation.

中文翻译：

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有丝分裂检查点复合体控制 Cdc20 调节蛋白与有丝分裂中泛素连接酶 APC/C 的关联


泛素连接酶后期促进复合物/环体（APC/C）及其调节蛋白Cdc20在有丝分裂不同阶段的控制中发挥重要作用。与 Cdc20 相关的 APC/C 具有活性，并通过靶向后期启动的降解抑制剂来促进中期 - 后期转变。在有丝分裂早期，有丝分裂检查点（或纺锤体组装检查点）系统可防止 APC/C 过早发挥作用，从而确保在所有染色体正确附着到有丝分裂纺锤体之前不会启动后期。活跃的有丝分裂检查点系统促进有丝分裂检查点复合物 (MCC) 的组装，MCC 与 APC/C 结合并抑制其活性。 Cdc20 与 APC/C 结合，大大增强了 MCC 与 APC/C 的相互作用。虽然已知 Cdc20 与 APC/C 的结合对于有丝分裂的这两个阶段都是至关重要的，但尚不清楚 Cdc20 如何在持续的过程、磷酸化和泛素化刺激其从 APC/C 中释放的情况下保持结合。我们发现，MCC 通过有丝分裂蛋白激酶 Cdk1-cyclin B 的作用，强烈抑制 APC/C 释放 Cdc20。这并不是由于 Cdc20 中影响其与 APC/C 相互作用的特定位点磷酸化受到保护。相反，MCC 可以稳定部分磷酸化形式的 Cdc20 与 APC/C 的结合。 MCC 还抑制 APC/C 结合的 Cdc20 的自身泛素化及其泛素化促进的 APC/C 释放。我们认为，MCC 在有丝分裂中维持 Cdc20 与 APC/C 结合的这些作用对于在有丝分裂检查点活动和随后的后期启动期间控制有丝分裂至关重要。