Abstract：
The anaphase-promoting complex/cyclosome (APC/C) is a critical and tightly regulated E3 ligase that orchestrates the cellular life cycle by controlling the degradation of cell cycle regulators. An intriguing feature of this complex is an autoinhibition mechanism: an intrinsically disordered loop domain, Apc1-300L, blocks Cdc20 coactivator binding, yet phosphorylation of Apc1-300L counteracts this autoinhibition. Many such disordered loops within APC/C remain unexplored. Our systematic analysis of loop-deficient APC/C mutants uncovered a pivotal role for Apc8\'s C-terminal loop (Apc8-L) in mitotic activation. Apc8-L directly recruits the CDK adaptor protein, Xe-p9/Cks2, positioning the Xe-p9-CDK-CycB complex near Apc1-300L. This stimulates the phosphorylation and removal of Apc1-300L, prompting the formation of active APC/CCdc20. Strikingly, without both Apc8-L and Apc3-L, the APC/C is rendered inactive during mitosis, highlighting Apc8-L\'s synergistic role with other loops and kinases. This study broadens our understanding of the intricate dynamics in APC/C regulation and provides insights on the regulation of macromolecular complexes.
摘要：
后期促进复合物/环小体（APC/C）是一种关键且受严格调节的E3连接酶，可通过控制细胞周期调节剂的降解来协调细胞生命周期。这个复合物的一个有趣的特征是自动抑制机制：一个内在无序的环域，Apc1-300L,阻断Cdc20共激活因子结合，然而Apc1-300L的磷酸化抵消了这种自动抑制。APC/C内的许多此类无序回路仍未被探索。我们对缺乏环的APC/C突变体的系统分析揭示了Apc8的C末端环（Apc8-L）在有丝分裂激活中的关键作用。Apc8-L直接募集CDK衔接蛋白，Xe-p9/Cks2，将Xe-p9-CDK-CycB复合物定位在Apc1-300L附近。这刺激了Apc1-300L的磷酸化和去除，促使形成活性APC/CCdc20。引人注目的是，没有Apc8-L和Apc3-L，APC/C在有丝分裂期间变得不活跃，强调Apc8-L与其他环和激酶的协同作用。这项研究拓宽了我们对APC/C调节中复杂动力学的理解，并提供了对大分子复合物调节的见解。
