Abstract
The ubiquitin (Ub)-proteasome system is vital to nearly every biological process in eukaryotes. Specifically, the conjugation of Ub to target proteins by Ub ligases, such as the Anaphase-Promoting Complex/Cyclosome (APC/C), is paramount for cell cycle transitions as it leads to the irreversible destruction of cell cycle regulators by the proteasome. Through this activity, the RING Ub ligase APC/C governs mitosis, G1, and numerous aspects of neurobiology. Pioneering cryo-EM, biochemical reconstitution, and cell-based studies have illuminated many aspects of the conformational dynamics of this large, multi-subunit complex and the sophisticated regulation of APC/C function. More recent studies have revealed new mechanisms that selectively dictate APC/C activity and explore additional pathways that are controlled by APC/C-mediated ubiquitination, including an intimate relationship with chromatin regulation. These tasks go beyond the traditional cell cycle role historically ascribed to the APC/C. Here, we review these novel findings, examine the mechanistic implications of APC/C regulation, and discuss the role of the APC/C in previously unappreciated signaling pathways.
Highlights
The post-translational modification of cellular proteins with ubiquitin (Ub) is a predominant form of eukaryotic regulation (Rape, 2018)
A subsequent structure of APC/CMCC bound to Cyclin A-CDK2Cks2 proposed a mechanism by which Cyclin A circumvents mitotic checkpoint complex (MCC) inhibition of the Anaphase-Promoting Complex/Cyclosome (APC/C) through multiple, disruptive interactions (Figure 4A)
Our work demonstrated that Cezanne levels peak during mitosis, in concert with APC/C activity, and that Cezanne interacts with, deubiquitinates, and opposes the degradation of APC/C substrates, including Aurora A and Cyclin B (Bonacci et al, 2018)
Summary
The post-translational modification of cellular proteins with ubiquitin (Ub) is a predominant form of eukaryotic regulation (Rape, 2018). Both inhibitors attach to the APC/C at specific sites to selectively modulate substrate binding and Ub transfer by the E2s, and are regulated by ubiquitination-dependent degradation, releasing the APC/C from their inhibition. Both high-resolution structural studies identified a previously undiscovered APC/CMCC “open” conformation in which CDC20A remains in contact with BUBR1 and CDC20M to prevent substrate recognition (Figure 3C; Alfieri et al, 2016; Yamaguchi et al, 2016).
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