Research Institute of Molecular Pathology, Vienna, Austria.
Nat Struct Mol Biol. 2012 Nov;19(11):1116-23. doi: 10.1038/nsmb.2412. Epub 2012 Sep 24.
The anaphase-promoting complex/cyclosome (APC/C) bound to CDC20 (APC/C(CDC20)) initiates anaphase by ubiquitylating B-type cyclins and securin. During chromosome bi-orientation, CDC20 assembles with MAD2, BUBR1 and BUB3 into a mitotic checkpoint complex (MCC) that inhibits substrate recruitment to the APC/C. APC/C activation depends on MCC disassembly, which was proposed to require CDC20 autoubiquitylation. Here we characterize APC15, a human APC/C subunit related to yeast Mnd2. APC15 is located near APC/C's MCC binding site; it is required for APC/C-bound MCC (APC/C(MCC))-dependent CDC20 autoubiquitylation and degradation and for timely anaphase initiation but is dispensable for substrate ubiquitylation by APC/C(CDC20) and APC/C(CDH1). Our results support the model wherein MCC is continuously assembled and disassembled to enable rapid activation of APC/C(CDC20) and CDC20 autoubiquitylation promotes MCC disassembly. We propose that APC15 and Mnd2 negatively regulate APC/C coactivators and report generation of recombinant human APC/C.
着丝粒-动粒复合物/细胞周期后期促进复合物（APC/C）与 CDC20（APC/C（CDC20））结合，通过泛素化 B 型细胞周期蛋白和 securin 来启动后期。在染色体双定向过程中，CDC20 与 MAD2、BUBR1 和 BUB3 组装成有丝分裂检查点复合物（MCC），抑制底物募集到 APC/C。APC/C 的激活依赖于 MCC 的解组装，据推测这需要 CDC20 的自泛素化。在这里，我们对人类 APC/C 亚基 APC15 进行了表征，它与酵母 Mnd2 有关。APC15 位于 APC/C 的 MCC 结合位点附近；它是 APC/C 结合的 MCC（APC/C（MCC））依赖的 CDC20 自泛素化和降解所必需的，并且对于及时启动后期是必需的，但对于 APC/C（CDC20）和 APC/C（CDH1）介导的底物泛素化是可有可无的。我们的结果支持这样的模型，即 MCC 不断地组装和解组装，以实现 APC/C（CDC20）的快速激活，并且 CDC20 的自泛素化促进 MCC 的解组装。我们提出 APC15 和 Mnd2 负调控 APC/C 共激活因子，并报告重组人 APC/C 的生成。
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