Polyanions provide selective control of APC/C interactions with the activator subunit

Abstract

ABSTRACTTransient interactions between the Anaphase-Promoting Complex/Cyclosome (APC/C) and its activator subunit Cdc20 or Cdh1 generate oscillations in ubiquitination activity necessary to maintain the order of cell cycle events. Activator binds the APC/C with high affinity and exhibits negligible dissociation kinetics in vitro, and it is not clear how the rapid turnover of APC/C-activator complexes is achieved in vivo. Here, we describe a mechanism that controls APC/C-activator interactions based on the availability of substrates. We find that APC/C-activator dissociation is stimulated by abundant cellular polyanions such as nucleic acids and polyphosphate. Polyanions also interfere with the ubiquitination of low-affinity substrates. However, engagement with high-affinity substrates blocks the inhibitory effects of polyanions on activator binding and APC/C activity. This mechanism amplifies the effects of substrate affinity on APC/C function, stimulating processive ubiquitination of high-affinity substrates and suppressing ubiquitination of low-affinity substrates.