The C-terminal disordered loop domain of Apc8 unlocks APC/C mitotic activation.

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/C^Cdc20. 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. [Display omitted] • Systematic analysis of APC/C uncovers a role for Apc8's C-terminal loop (Apc8-L) • Apc8-L directly recruits Cks2-CDK and activates APC/C via a phosphorylation relay • Apc8-L and Apc3-L cooperatively activate mitotic APC/C • Apc8-L and Apc3-L dual pathways shed light on new therapeutic insights Darling et al. explore APC/C regulation by disordered loops, uncovering the Apc8-loop's role in mitotic APC/C activation, via kinase recruitment and synergistic cooperation with other loops, refining established cell cycle control mechanisms. This study suggests these loops are key to understanding APC/C dynamics, paving the way for potential therapeutic explorations. [ABSTRACT FROM AUTHOR]