Intricate Regulatory Mechanisms of the Anaphase-Promoting Complex/Cyclosome and Its Role in Chromatin Regulation

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.

Counting Degrons: Lessons From Multivalent Substrates for Targeted Protein Degradation

“…Nonetheless the idea that the affinity of APC/C-substrate interactions is crucial to understanding how the APC/C “orders” the degradation of its substrates remains central. Recent reviews of this question have discussed proposed mechanisms that include co-activator switching, fine-tuning of APC/C-substrate interactions by phosphorylation or other post-translational modifications, differential processivity of ubiquitination, and substrate competition ( Davey and Morgan, 2016 ; Alfieri et al, 2017 ; Bodrug et al, 2021 ).…”

Genetic Determinants of Biomass in C4 Crops: Molecular and Agronomic Approaches to Increase Biomass for Biofuels

“…Another essential component of cell cycle machinery is the anaphase-promoting complex (APC), a multi-subunit E3 ligase that modulates cyclins (Cyc) and CDKs activity in checkpoints to ensure the maintenance of cell division rate ( Bodrug et al, 2021 ). APC/C-subunits remain conserved throughout evolution, however, gene duplication of different subunits has been observed in some plants ( de Lima et al, 2010 ).…”

Examining the mechanistic relationship of APC/CCDH1 and its interphase inhibitor EMI1

“…4,5 An essential, cell cycle-regulated Ub ligase is the 1.2 MDa Anaphase-Promoting Complex/Cyclosome (APC/C). 6,7 The APC/C has numerous notable cell cycle targets, such as securin and cyclin B, and is responsible for controlling the mitotic checkpoint and the maintenance of G1. [8][9][10][11][12][13][14] The APC/C is then shut down to permit S phase entry.…”

“…Similar to other RING E3 Ub ligases, the largest family of Ub ligases, the APC/C serves as a scaffold to simultaneously bind both a substrate and Ub-conjugating enzymes (E2s). 7,27,28 APC/C recognizes substrates through short motifs called degrons, such as the destruction box (D-box) and KEN-box. [29][30][31][32] APC/C also recruits its associated E2s, UBE2C, and UBE2S, to facilitate Ub transfer: once bound to the APC/C catalytic module, UBE2C first primes the substrate with Ub on substrate lysines or forms short Ub chains, while UBE2S extends K11-linked Ub chains.…”

“…Similar to other RING E3 Ub ligases, the largest family of Ub ligases, the APC/C serves as a scaffold to simultaneously bind both a substrate and Ub‐conjugating enzymes (E2s) 7,27,28 . APC/C recognizes substrates through short motifs called degrons, such as the destruction box (D‐box) and KEN‐box 29–32 .…”