# Anaphase-promoting complex
The anaphase-promoting complex, also called the cyclosome (APC/C), is a multi-subunit E3 ubiquitin ligase (enzyme that tags proteins with ubiquitin for destruction) that drives the eukaryotic cell cycle by tagging key regulatory proteins, notably cyclin B and securin, for destruction by the 26S proteasome[1](https://www.nature.com/articles/nrm1988). It initiates sister-chromatid separation and exit from mitosis, and its activity is required again in G1 phase before [DNA replication](https://www.edgepedia.org/dna-replication) can begin[1](https://www.nature.com/articles/nrm1988). With more than a dozen subunits assembled into a complex of about 1.5 MDa, it has been described as the most complex molecular machine known to catalyze ubiquitylation reactions[1](https://www.nature.com/articles/nrm1988).
| Key fact | Detail |
|---|---|
| Classification | Multi-subunit cullin-RING E3 ubiquitin ligase (EC 2.3.2.27), the partner of the SCF complex in cell-cycle proteolysis[2](https://pubmed.ncbi.nlm.nih.gov/21092369/) • [3](https://pmc.ncbi.nlm.nih.gov/articles/PMC3206288/) |
| Size and composition | About 1.5 MDa, more than a dozen subunits; 13 core subunits in yeast[1](https://www.nature.com/articles/nrm1988) • [3](https://pmc.ncbi.nlm.nih.gov/articles/PMC3206288/) |
| Principal substrates | Cyclin B and securin, whose destruction triggers anaphase and mitotic exit; mitotic cyclins generally[1](https://www.nature.com/articles/nrm1988) • [4](https://www.sciencedirect.com/science/article/pii/S0960982204006967) |
| Co-activators | Cdc20 (active in mitosis) and Cdh1 (active in G1), WD40-domain proteins that bind substrate destruction boxes (D-boxes)[1](https://www.nature.com/articles/nrm1988) |
| Ubiquitin chains | Assembles atypical Lys11-linked chains in metazoans, initiated by Ube2C/UbcH10 and elongated by Ube2S; K48-linked chains are also formed[5](https://pmc.ncbi.nlm.nih.gov/articles/PMC5717348/) • [6](https://pmc.ncbi.nlm.nih.gov/articles/PMC6534075/) |
| Architecture | Triangular particle of roughly 200–230 Å with a central cavity; three modules: central scaffold (APC1, APC4, APC5), catalytic arm (APC2, APC11), and TPR structural arm (APC3, APC6, APC7, APC8)[7](https://pmc.ncbi.nlm.nih.gov/articles/PMC3203452/) • [8](https://doi.org/10.1146/annurev-cellbio-120420-092421) |
| Structural milestones | First atomic cryo-EM structures with coactivator and E2 or Emi1 in 2015; human APC/CCDH1:EMI1 and apo-APC/C maps at 2.9 Å and 3.2 Å in 2024[9](https://www.nature.com/articles/nature14471) • [10](https://www.nature.com/articles/s41467-024-54398-5) |
## Function in the cell cycle
The APC/C was originally identified as the E3 activity responsible for degrading mitotic cyclins, and its name reflects a second role, the ubiquitination of the anaphase inhibitor securin[4](https://www.sciencedirect.com/science/article/pii/S0960982204006967). Destruction of cyclin B and securin by the 26S proteasome initiates sister-chromatid separation and exit from mitosis[1](https://www.nature.com/articles/nrm1988). During S and G2 phases the APC/C remains inactive, allowing mitotic cyclins to accumulate; once chromosomes have aligned properly, the complex is activated and ubiquitinates its targets, forming an integral part of the machinery that gives the cell cycle its periodicity[11](https://link.springer.com/content/pdf/10.1007/s00018-015-2096-7.pdf).
**A second role in replication.** APC/C activity is indirectly required for DNA replication: cyclin degradation inactivates cyclin-dependent kinase 1 (Cdk1), and low Cdk1 activity is a prerequisite for assembly of pre-replication complexes[1](https://www.nature.com/articles/nrm1988). In dividing cells the APC/C orchestrates progression through mitosis and G1, while the related SCF ligase operates at all stages of the cell cycle[3](https://pmc.ncbi.nlm.nih.gov/articles/PMC3206288/).
## Substrate recognition
Selection of APC/C targets depends on short destruction motifs, predominantly the D-box and the KEN-box[2](https://pubmed.ncbi.nlm.nih.gov/21092369/). All known co-activators contain a propeller-shaped WD40 domain that interacts with the D-box of substrates[1](https://www.nature.com/articles/nrm1988). Co-activators are required but not sufficient for substrate recognition: the Apc10/Doc1 subunit is also needed, and evidence suggests the D-box interacts with both co-activator and core subunits to form a ternary complex in which ubiquitylation occurs[1](https://www.nature.com/articles/nrm1988). Co-activators also increase catalytic efficiency, lowering the apparent Km and raising Vmax for yeast APC/C[5](https://pmc.ncbi.nlm.nih.gov/articles/PMC5717348/).
## Co-activators and the relay through the cycle
APC/C is activated by proteins of the Cdc20/Cdh1 family, and the interaction is controlled by phosphorylation and restricted to mitosis and G1[1](https://www.nature.com/articles/nrm1988). Cdk1-dependent phosphorylation of Cdh1 is inhibitory, which represses Cdh1 action in mitosis and makes Cdc20 the predominant co-activator at that stage[6](https://pmc.ncbi.nlm.nih.gov/articles/PMC6534075/). During anaphase and telophase, APC/C contributes to degradation of securin and cyclin B and destroys additional substrates such as Polo-like kinase 1 and Cdc20 itself, the degradation of which diminishes APC/C activity and facilitates the transition to APC/C; the resulting drop in Cdk1 activity promotes APC/C formation, which maintains cyclin instability through G1 and permits a new round of DNA replicationCdh1 contributes to degradation of securin and cyclin B and destroys additional substrates such as Polo-like kinase 1 and Cdc20 itself, which inactivates APC/CCdc20; the resulting drop in Cdk1 activity promotes APC/CCdh1 formation, which maintains cyclin instability through G1 and permits a new round of DNA replication[12](https://mcb.berkeley.edu/courses/mcb230/WEB/PAPERS/apc.pdf) • [18](https://journals.asm.org/doi/10.1128/jvi.00088-13). The functional switching between Cdc20 and Cdh1 has been described as a "relay control" mechanism, with the core switch at late mitosis[13](https://www.sciencedirect.com/science/article/abs/pii/S0898656825005868).
## Inhibition and checkpoints
Several inhibitory proteins restrain APC/C activity. Mad2 and BubR1 inhibit the complex during spindle assembly, preventing precocious initiation of anaphase and mitotic exit before all chromosomes are properly attached; the spindle assembly checkpoint delays mitotic progression by preventing activation of APC/C by Cdc20[1](https://www.nature.com/articles/nrm1988) • [14](https://arxiv.org/abs/1701.04316). Members of the EMI1/RCA1 family inhibit the APC/C from S phase until early mitosis, and during meiosis in vertebrate eggs[1](https://www.nature.com/articles/nrm1988). Auto-ubiquitination of Cdc20 bound to the mitotic checkpoint complex contributes to the reciprocal regulation of APC/C and the checkpoint[5](https://pmc.ncbi.nlm.nih.gov/articles/PMC5717348/).
## Structure and catalytic mechanism
Electron microscopy showed that the APC/C resembles a triangular structure of approximately 200–230 Å with a central cavity surrounded by a protein wall[7](https://pmc.ncbi.nlm.nih.gov/articles/PMC3203452/). The complex divides into three domains: a central scaffolding platform of APC1, APC4, and APC5; a catalytic arm of APC2 and APC11, with the RING subunit APC11 recruiting the E2 enzyme; and a structural arm of tetratricopeptide-repeat proteins APC8, APC6, APC3, and APC7, present as dimers, which binds the co-activator and Apc10[8](https://doi.org/10.1146/annurev-cellbio-120420-092421). Like the SCF, the APC/C is a cullin-RING ligase in which the RING protein (Apc11) is anchored by a cullin scaffold (Apc2)[3](https://pmc.ncbi.nlm.nih.gov/articles/PMC3206288/).
**Two E2 enzymes.** Metazoan APC/C assembles atypical Lys11-linked ubiquitin chains using two E2s in series: a chain-initiating enzyme such as Ube2C/UbcH10, which binds the RING subunit Apc11 and Apc2 and transfers the first ubiquitins, and an elongating enzyme, Ube2S, which binds Apc2 and Apc4 through its C-terminal LRRL tail and extends K11-linked chains. Ube2S elongates through a substrate-assisted catalytic mechanism in which Glu34 on the acceptor ubiquitin orients the target Lys11; the two E2s acting together can generate branched chains with mixed K11 and K48 linkages[5](https://pmc.ncbi.nlm.nih.gov/articles/PMC5717348/) • [6](https://pmc.ncbi.nlm.nih.gov/articles/PMC6534075/).
**Atomic structures.** In 2015, cryo-electron microscopy yielded atomic structures of human APC/C bound to Cdh1 with either the inhibitor Emi1 or a UbcH10-ubiquitin conjugate, defining the architecture of all subunits and explaining how Emi1 inhibits both E2 enzymes[9](https://www.nature.com/articles/nature14471). In 2024, improved cryo-EM structures of human APC/CCDH1:EMI1 and apo-APC/C were determined at 2.9 Å and 3.2 Å resolution, respectively[10](https://www.nature.com/articles/s41467-024-54398-5).
## Beyond mitosis
APC/C functions extend outside cell-cycle control. It regulates a range of differentiation processes, from cell fate specification in progenitor cells to terminal differentiation of specific cell types, by controlling degradation of cell type-specific transcriptional regulators, modulating responses to signaling pathways, and regulating centrosome organization[15](https://www.sciencedirect.com/science/article/abs/pii/S0962892419300443). Broader reviews list roles in genome stability, energy metabolism, cell death, autophagy, and carcinogenesis[16](https://celldiv.biomedcentral.com/articles/10.1186/s13008-016-0021-6). Deregulation of the proteolytic system can result in uncontrolled proliferation, genomic instability, and cancer, and alterations in ubiquitylation of cell-cycle regulators have been documented in many human malignancies[17](https://doi.org/10.1038/nrc1881). Plants possess their own APC/C with additional regulators, including inhibitors such as UVI4, UBP14, and OSD1, and likely activators such as SAMBA and TDM1[8](https://doi.org/10.1146/annurev-cellbio-120420-092421).
## References
1. [Peters, J.-M. (2006). The anaphase promoting complex/cyclosome: a machine designed to destroy. Nature Reviews Molecular Cell Biology 7, 644–656.](https://www.nature.com/articles/nrm1988)
2. [Barford, D. (2011). Structure, function and mechanism of the anaphase promoting complex (APC/C). Quarterly Reviews of Biophysics 44, 153–190.](https://pubmed.ncbi.nlm.nih.gov/21092369/)
3. [The multiple layers of ubiquitin-dependent cell cycle control. PMC.](https://pmc.ncbi.nlm.nih.gov/articles/PMC3206288/)
4. [Vodermaier, H. C. (2004). APC/C and SCF: Controlling Each Other and the Cell Cycle. Current Biology 14, R787–R796.](https://www.sciencedirect.com/science/article/pii/S0960982204006967)
5. [Visualizing the complex functions and mechanisms of the anaphase promoting complex/cyclosome (APC/C). PMC.](https://pmc.ncbi.nlm.nih.gov/articles/PMC5717348/)
6. [APC/C: current understanding and future perspectives. PMC.](https://pmc.ncbi.nlm.nih.gov/articles/PMC6534075/)
7. [Structural insights into anaphase-promoting complex function and mechanism. PMC.](https://pmc.ncbi.nlm.nih.gov/articles/PMC3203452/)
8. [The Plant Anaphase-Promoting Complex/Cyclosome. Annual Review of Cell and Developmental Biology.](https://doi.org/10.1146/annurev-cellbio-120420-092421)
9. [Chang, L. et al. (2015). Atomic structure of the APC/C and its mechanism of protein ubiquitination. Nature 522, 450.](https://www.nature.com/articles/nature14471)
10. [Cryo-EM structures of apo-APC/C and APC/C^CDH1:EMI1 complexes provide insights into APC/C regulation. Nature Communications 15, 10074 (2024).](https://www.nature.com/articles/s41467-024-54398-5)
11. [Cyclin degradation and APC/C in the cell cycle. Cellular and Molecular Life Sciences.](https://link.springer.com/content/pdf/10.1007/s00018-015-2096-7.pdf)
12. [APC/C^Cdh1 activity during anaphase, telophase, and G1. MCB course paper, UC Berkeley.](https://mcb.berkeley.edu/courses/mcb230/WEB/PAPERS/apc.pdf)
13. [APC/C coactivators Cdh1 and Cdc20: Mechanistic insights into cancer progression and therapeutic opportunities. ScienceDirect (2025).](https://www.sciencedirect.com/science/article/abs/pii/S0898656825005868)
14. [Spindle assembly checkpoint is sufficient for complete Cdc20 sequestering in mitotic control. arXiv.](https://arxiv.org/abs/1701.04316)
15. [APC/C Ubiquitin Ligase: Coupling Cellular Differentiation to G1/G0 Phase in Multicellular Systems. Trends in Cell Biology 29, 591–603 (2019).](https://www.sciencedirect.com/science/article/abs/pii/S0962892419300443)
16. [Insights into APC/C: from cellular function to diseases and therapeutics. Cell Division (2016).](https://celldiv.biomedcentral.com/articles/10.1186/s13008-016-0021-6)
17. [Nakayama, K. I. & Nakayama, K. (2006). Ubiquitin ligases: cell-cycle control and cancer. Nature Reviews Cancer 6, 369–381.](https://doi.org/10.1038/nrc1881)
18. [journals.asm.org](https://journals.asm.org/doi/10.1128/jvi.00088-13)
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*Topic: Encyclopedia › Life and health › Biological foundations › Biochemistry and metabolism › Protein families and complexes › Biomolecular complexes and assemblies › Proteasome and ubiquitin-system assemblies*
*Initially written Sep 17, 2026 · Reviewed: Sep 30, 2026; Oct 21, 2026 · Edited: Sep 30, 2026; Oct 21, 2026 · Last review: Oct 21, 2026*
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