Hubbry Logo
Anaphase-promoting complexAnaphase-promoting complexMain
Open search
Anaphase-promoting complex
Community hub
Anaphase-promoting complex
logo
8 pages, 0 posts
0 subscribers
Be the first to start a discussion here.
Be the first to start a discussion here.
Anaphase-promoting complex
Anaphase-promoting complex
Anaphase-promoting complex
View on Wikipedia
from Wikipedia
The anaphase-promoting complex (APC) is a large protein complex containing 11–13 subunits, including a RING subunit (Apc11) and a cullin (Apc2). APC activity requires association with activator subunits (Cdc20 or Cdh1) that contribute to substrate binding.

Anaphase-promoting complex (also called the cyclosome or APC/C) is an E3 ubiquitin ligase that marks target cell cycle proteins for degradation by the 26S proteasome. The APC/C is a large complex of 11–13 subunit proteins, including a cullin (Apc2) and RING (Apc11) subunit much like SCF. Other parts of the APC/C have unknown functions but are highly conserved.[1]

It was the discovery of the APC/C (and SCF) and their key role in eukaryotic cell-cycle regulation that established the importance of ubiquitin-mediated proteolysis in cell biology. Once perceived as a system exclusively involved in removing damaged protein from the cell, ubiquitination and subsequent protein degradation by the proteasome is now perceived as a universal regulatory mechanism for signal transduction whose importance approaches that of protein phosphorylation.

In 2014, the APC/C was mapped in 3D at a resolution of less than a nanometre, which also uncovered its secondary structure. This finding could improve understanding of cancer and reveal new binding sites for future cancer drugs.[2][3]

Function

[edit]
M–Cdk activity promotes the events of early mitosis, resulting in the metaphase alignment of sister chromatids on the spindle. M–Cdk activity also promotes the activation of APCCdc20, which triggers anaphase and mitotic exit by stimulating the destruction of regulatory proteins, such as securin and cyclins, that govern these events. By promoting cyclin destruction and thus Cdk inactivation, APCCdc20 also triggers activation of APCCdh1, thereby ensuring continued APC activity in G1.

The APC/C's main function is to trigger the transition from metaphase to anaphase by tagging specific proteins for degradation. The three major targets for degradation by the APC/C are securin and S and M cyclins. Securin releases separase, a protease, when degraded. Separase then triggers the cleavage of cohesin, the protein complex that binds sister chromatids together. During metaphase, sister chromatids are linked by intact cohesin complexes. When securin undergoes ubiquitination by the APC/C and releases separase, which degrades cohesin, sister chromatids become free to move to opposite poles for anaphase. The APC/C also targets the mitotic cyclins for degradation, resulting in the inactivation of M-CDK (mitotic cyclin-dependent kinase) complexes, promoting exit from mitosis and cytokinesis.[1]

Unlike the SCF, activator subunits control the APC/C. Cdc20 and Cdh1 are the two activators of particular importance to the cell cycle. These proteins target the APC/C to specific sets of substrates at different times in the cell cycle, thus driving it forward. The APC/C also plays an integral role in the maintenance of chromatin metabolism, particularly in G1 and G0, and plays a key role in phosphorylation of H3 through destruction of the aurora A kinase.[4]

The critical substrates of the APC/C appear to be securin and the B type cyclins. This is conserved between mammals and yeast. In fact, yeast are viable in the absence of the APC/C if the requirement for targeting these two substrates is eliminated.[5]

Subunits

[edit]

There is not a vast amount of extensive investigation on APC/C subunits, which serve mostly as adaptors. Studies of APC subunits are mainly conducted in yeast, and studies show that the majority of yeast APC subunits are also present in vertebrates, this suggests conservation across eukaryotes. Eleven core APC subunits have been found in vertebrates versus thirteen in yeast.[1] Activator subunits bind to APC at varying stages of the cell cycle to control its ubiquitination activity, often by directing APC to target substrates destined for ubiquitination. The specificity of APC ligases is proposed to be controlled by the incorporation of specificity factors into the ligase complex, instead of substrate phosphorylation. i.e.: The subunit, CDC20 allows APC to degrade substrates such as anaphase inhibitors (Pdsp1) at the beginning of anaphase, on the other hand when CDC20 is substituted for specificity factor Hct1, APC degrades a different set of substrates, particularly mitosis cyclins in late anaphase. Activators CDC20 and Cdh1 are of particular significance and are the most widely studied and familiar of the APC/C subunits.

The catalytic core of the APC/C consists of the cullin subunit Apc2 and RING H2 domain subunit Apc11. These two subunits catalyze ubiquitination of substrates when the C-terminal domain of Apc2 forms a tight complex with Apc11. RING/APc11 binds to the E2-ubiquitin conjugate that catalyzes the transfer of ubiquitin to an active site in E2.[1] In addition to the catalytic functionality, other core proteins of the APC are composed multiple repeat motifs with the main purpose of providing molecular scaffold support. These include Apc1, the largest subunit which contains 11 tandem repeats of 35–40 amino acid sequences, and Apc2, which contains three cullin repeats of approximately 130 amino acids total.[6] The major motifs in APC subunits include tetratricopeptide (TPR) motifs and WD40 repeats 1.[1] C-termini regions of CDC20 and Cdh1 have a WD40 domain that is suggested to form a binding platform that binds APC substrates, thus contributing to APCs ability to target these substrates, although the exact mechanism through which they increase APC activity is unknown.[7] It is also suggested that variations in these WD40 domains result in varying substrate specificity, which is confirmed by recent results suggesting that different APC substrates can directly and specifically bind to Cdc20 and Cdh1/Hct1 Ultimately, the specificity differences are responsible for the timing of the destruction of several APC targets during mitosis. With CDC20 targeting a few major substrates at metaphase and Cdh1 targeting a broader range of substrates towards late mitosis and G1.[8]

Most notably, 4 subunits of yeast APC/C consist almost entirely of multiple repeats of the 34 amino acid tetratricopeptide residue (TPR) motif. These TPR subunits, Cdc16,[9] Cdc27,[10] Cdc23, and Apc5, mainly provide scaffolding and support to mediate other protein-protein interactions. Cdc27 and Cdc23 have been shown to support the binding of Cdc20 and Cdh1, as mutations in key residues of these subunits led to increased dissociation of the activators. Apc10/Doc1, has been shown to promote substrate binding by mediating their interactions with Cdh1 and Cdc20.[11]

In particular, CDC20 (also known as p55CDC, Fizzy, or Slp1) inactivates CDK1 via ubiquitination of B-type cyclins. This results in activation of Cdh1(a.k.a. Fizzy-related, Hct1, Ste9, or Srw1), which interacts with APC during late mitosis and G1/G0. Cdh1 is inactivated via phosphorylation during S, G2 and early M phase. During these points in the cycle, it is not able to be assembled.[12]

Evidence shows that APC3 and APC7 serve to recruit Cdh1 to the anaphase-promoting complex.[13] This further supports that Cdh1 is responsible for maintaining APC activity during G1. Cdh1 does not require APC to be phosphorylated in order to bind, in fact, phosphorylation of Cdh1 by Cdks prevents it from binding to APC from S to M phase. With destruction of M-Cdk, release of CDC20 from the APC and binding of Cdh1 can now occur, allowing APC activity to continue on during G1 entry.[1] While Cdh1 recognizes M and S cyclins, allowing for their destruction until the entire cell commits to proceed to a new cycle, it does not recognize G1/S cyclins, and during G1/S phase, their cyclin activity can rise unhindered and phosphorylate and thus inactivating Cdh1 and therefore APC.

The subunit Apc15 plays an important role in APC/CCdc20 activation following the bi-orientation of sister chromatids across the metaphase plate. When kinetochores are unattached to spindles, mitotic checkpoint complexes (MCC) and inhibit APC. In the absence of Apc15, MCCs and Cdc20 remain locked on the APC/C preventing its activity once the spindle checkpoint requirements are met. Apc15 mediates the turnover of Cdc20 and MCCs to provide information on the attachment state of kinetochores.[14]

CDC27/APC3

[edit]

One of the subunits that exhibit the TPR motif, CDC27 has been identified to interact with mitotic checkpoint proteins such as Mad2, p55CDC and BUBR1, suggesting that it may have involvement in the timing of M phase.[15] Evidence shows that CDC27 is involved in a ternary complex with SMAD2/3 and Cdh1, which is created in response to TGFβ signalling. Because of its interaction with Cdh1 in particular, it has a potential role in determining affinity between APC and its activators Cdc20 and Cdh1. A study suggests that TGF-β-induced Cdc27 phosphorylation enhances interaction between cdc27 and Cdh1–which is directly involved in activating APC.[16] CDC27 can serve as a vehicle through which TGFβ signalling can activate APC. Induced CDC27 hyperphosphorylation by TGFβ showed elevated APC activity.

CDC23, CDC16, CDC27

[edit]

CDC23, another TPR subunit interacts with SWM1, binding to the D-box of CLB2. Based upon hybrid assays in vivo and co-immunoprecipitation in vitro, it is suggested that Cdc16p, Cdc23p and Cdc27p (analogs in Sacchyromyces cerevisiae) interact and form a macromolecular complex. Their common theme of TPR is suggested to mediate these interactions.[17] As for Cdc27 and Cdc16 in drosophila, their functions have been tested via RNA interference (RNAi).[18] Results suggest that they may mediate activity of the entire complex via different mechanisms at different sites. In further drosophila studies, Cdk16 and cdk23 appear to be activated via phosphorylation by Polo-like kinase 1 (Plk1) and its fission yeast counterpart, appear to bind particularly to Cdc23.[19]

The complex is understood to be regulated by activators CDC20 and Cdh1 during mitosis. Their role in degradation for cyclin B is demonstrated by a screen of Saccharomyces cerevisiae mutants defective for cyclin B degradation, which were found to have mutations in CDC16 and CDC23 genes. Mutants for CDC27, CDC23 and CDC 27 all resulted in a cell-cycle arrest at metaphase.[20]

Substrate recognition

[edit]

APC/C substrates have recognition amino acid sequences that enable the APC/C to identify them. The most common sequence is known as the destruction box or D-box. APC/C brings together an E2 ubiquitin-conjugating enzyme and the D-box rather than being an intermediate covalent carrier.[21] The D-box should have a version of the following amino acid sequence: RXXLXXXXN, where R is arginine, X is any amino acid, L is Leucine, and N is asparagine. The Ken-box is another motif of importance. Its sequence should resemble the one that follows: KENXXXN, where K is lysine and E is glutamate. The last amino acid position in the Ken-box is highly variable. Though it has been shown that mutations in the sequences do inhibit destruction of the proteins "in vivo", there is still much to learn about how proteins are targeted by the APC/C.[1]

Once bound to APC/C, Cdc20 and Cdh1 serve as D and KEN box receptors for various APC substrates. Kraft et al. have shown that the substrates' D boxes bind directly to the highly conserved WD40 repeat propeller region on the APC activators. It is important to note that the conserved area of the propeller of Cdh1 is much larger than that of Cdc20, allowing Cdh1 to have a broader substrate specificity, consistent with the fact that APC/CCdh1 also activates APC-mediated destruction of KEN box containing substrates. The D box further enhances protein degradation, for Lysine residues in close proximity to the D box serve as targets of ubiquitylation. It has been found that a Lys residue immediately C-terminal to the D box can function as a ubiquitin acceptor.[22]

Many APC substrates contain both D and KEN boxes, with their ubiquitylation by either APC/CCdc20 or APC/CCdh1 dependent on both sequences, yet some substrates contain only either a D box or a KEN box, in one or multiple copies. Having two distinct degradation sequences creates a high level of substrate specificity on the APC/C, with APC/CCdc20 being more dependent on the D box and APC/CCdh1 more dependent on the KEN box. For example, APC/CCdh1 is capable of ubiquitylating KEN box-only-containing substrates like Tome-1 and Sororin.[6]

Although Cdc20 and Cdh1 may serve as D and KEN box receptors, the low affinity of these co-activator–substrate interactions suggests that it is unlikely that the co-activators alone are sufficient to confer high-affinity substrate binding to the APC/CCdc20 and APC/CCdh1.[6] Consequently, core APC/C subunits, like Apc10, contribute towards substrate association as well. In APC/C constructs lacking the Apc10/Doc1 subunit, substrates like Clb2 are unable to associate with APCΔdoc1–Cdh1, while addition of purified Doc1 to the APCΔdoc1–Cdh1 construct restores the substrate binding ability.[11]

Metaphase to anaphase transition

[edit]

As metaphase begins, the spindle checkpoint inhibits the APC/C until all sister-kinetochores are attached to opposite poles of the mitotic spindle, a process known as chromosome biorientation. When all kinetochores are properly attached, the spindle checkpoint is silenced and the APC/C can become active. M-Cdks phosphorylate subunits on the APC/C that promote binding to Cdc20. Securin and M cyclins (cyclin A and cyclin B) are then targeted by APC/CCdc20 for degradation. Once degraded, separin is released, cohesin is degraded and sister chromatids are prepared to move to their respective poles for anaphase.[1]

It is likely that, in animal cells, at least some of the activation of APC/CCdc20 occurs early in the cell cycle (prophase or prometaphase) based on the timing of the degradation of its substrates. Cyclin A is degraded early in mitosis, supporting the theory, but cyclin B and securin are not degraded until metaphase. The molecular basis of the delay is unknown, but is believed to involve the key to the correct timing of anaphase initiation. In animal cells the spindle checkpoint system contributes to the delay if it needs to correct the bi-orientation of chromosomes. Though how the spindle checkpoint system inhibits cyclin B and securin destruction while allowing cyclin A to be degraded is unknown. The delay may also be explained by unknown interactions with regulators, localization and phosphorylation changes.[1]

This initiates a negative feedback loop. While activation of APC/CCdc20 requires M-Cdk, the complex is also responsible for breaking the cyclin to deactivate M-CdK. This means that APC/CCdc20 fosters its own deactivation. It is possible that this negative feedback is the backbone of Cdk activity controlled by M and S cyclin concentration oscillations.[1]

M to G1 transition

[edit]

Upon completion of mitosis, it is important that cells (except for embryonic ones) go through a growth period, known as G1 phase, to grow and produce factors necessary for the next cell cycle. Entry into another round of mitosis is prevented by inhibiting Cdk activity. While different processes are responsible for this inhibition, an important one is activation of the APC/C by Cdh1. This continued activation prevents the accumulation of cyclin that would trigger another round of mitosis and instead drives exit from mitosis.[1]

In the beginning of the cell cycle Cdh1 is phosphorylated by M-Cdk, preventing it from attaching to APC/C. APC/C is then free to attach to Cdc20 and usher the transition from metaphase to anaphase. As M-Cdk gets degraded later in mitosis, Cdc20 gets released and Cdh1 can bind to APC/C, keeping it activated through the M/G1 transition. A key difference to note is that while binding of Cdc20 to APC/C is dependent on phosphorylation of APC/C by mitotic Cdks, binding of Cdh1 is not. Thus, as APCCdc20 becomes inactivated during metaphase due to dephosphorylation resulting from inactive mitotic Cdks, Cdh1 is able to immediately bind to APC/C, taking Cdc20's place. Cdc20 is also a target of APC/CCdh1, ensuring that APC/CCdc20 is shut down. APC/CCdh1 then continues working in G1 to tag S and M cyclins for destruction. However, G1/S cyclins are not substrates of APC/CCdh1 and therefore accumulate throughout this phase and phosphorylate Cdh1. By late G1, enough of the G1/S cyclins have accumulated and phosphorylated Cdh1 to inactivate the APC/C until the next metaphase.[1]

Once in G1, APCCdh1 is responsible for the degradation of various proteins that promote proper cell cycle progression. Geminin is a protein that binds to Cdt1 which prevents its binding to the origin recognition complex (ORC). APCCdh1 targets geminin for ubiquitination throughout G1, keeping its levels low. This allows Cdt1 to carry out its function during pre-RC assembly. When APCCdh1 becomes inactive due to phosphorylation of Cdh1 by G1/S cyclins, geminin activity is increased again. Additionally, Dbf4 stimulates Cell division cycle 7-related protein kinase (Cdc7) activity, which promotes activation of replication origins. APCCdh1 is thought to target Dbf4 for destruction. This could provide an answer as to how Cdc7 is activated at the beginning of a new cell cycle. Its activity likely corresponds to the inactivation of APC/CCdh1 by G/S cyclins.[1]

Additional regulation

[edit]

APC/CCdc20 inactivation during early stages of the cell cycle is partially achieved by the protein Emi1. Initial experiments have shown that addition of Emi1 to Xenopus cycling extracts can prevent the destruction of endogenous cyclin A, cyclin B, and mitotic exit, suggesting that Emi1 is able to counteract the activity of the APC. Furthermore, depletion of Emi1 in somatic cells leads to the lack of accumulation of cyclin B. The lack of Emi1 likely leads to a lack of inhibition of the APC preventing cyclin B from accumulating.[23]

From these early observations, it has been confirmed that in G2 and early mitosis, Emi1 binds and inhibits Cdc20 by preventing its association with APC substrates. Cdc20 can still be phosphorylated and bind to APC/C, but bound Emi1 blocks Cdc20's interaction with APC targets.[1] Emi1 association with Cdc20 allows for the stabilization of various cyclins throughout S and G2 phase, but Emi1's removal is essential for progression through mitosis. Thus, in late prophase, Emi1 is phosphorylated by Polo-like kinase, Plk. Plk is activated during early mitosis by Cdk1 activity, and its phosphorylation of Emi1's BTRC (gene) βTrCP binding site makes it a target for SCF, leading to its subsequent destruction in prometaphase.[24] Emi1's destruction leads APC/CCdc20 activation, allowing for the destruction of cyclin A in early mitosis. Emi1 levels begin to rise again in G, which help inhibit APC/CCdh1.[1]

Regulation of APC/CCdc20 activity towards metaphase substrates like securin and cyclin B may be a result of intracellular localization. It is hypothesized that spindle checkpoint proteins that inhibit APC/CCdc20 only associate with a subset of the Cdc20 population localized near the mitotic spindle. In this manner, cyclin A can be degraded while cyclin B and securin are degraded only once sister chromatids have achieved bi-orientation.[1]

See also

[edit]

References

[edit]

Further reading

[edit]
[edit]
Revisions and contributorsEdit on WikipediaRead on Wikipedia

Anaphase-promoting complex

View on Grokipedia
from Grokipedia
The Anaphase-promoting complex (APC/C), also known as the cyclosome, is a multi-subunit cullin-RING that orchestrates progression by marking key regulatory proteins for ubiquitin-dependent proteasomal degradation, primarily during and the subsequent . This complex ensures the timely and irreversible transitions essential for cellular division, such as the onset of through the destruction of securin and B1, which respectively allow sister chromatid separation and inactivation of (CDK1). Composed of at least 13 core subunits—including scaffold proteins like APC1 and APC5, the cullin APC2, and the RING domain-containing APC11—APC/C requires co-activators such as CDC20 (active in to ) or CDH1 (active from through ) to recognize substrates via specific motifs like the D-box (RxxLxxxxN) or KEN box. Its activity is tightly regulated by mitotic , the spindle assembly checkpoint, and inhibitors such as EMI1, preventing premature degradation and maintaining genomic stability. Beyond mitosis, APC/C influences broader cellular processes, including , , and tumor suppression, by targeting a diverse array of substrates like , geminin, and Aurora kinases for degradation. Dysregulation of APC/C, often through mutations in co-activators like CDH1 (a tumor suppressor) or overexpression of CDC20 (an oncoprotein), is implicated in tumorigenesis, highlighting its role in preventing uncontrolled proliferation. Structurally, APC/C forms a large, asymmetric assembly resembling a pyramid, with the catalytic core at the base facilitating ubiquitin transfer from E2 enzymes like UBE2C, while the top platform binds co-activators and substrates. This architecture enables spatiotemporal control, ensuring APC/C activity aligns with checkpoint signals to drive unidirectional advancement. In evolutionary conserved terms, APC/C operates across eukaryotes, from (where it was first identified as a cyclin-degrading activity) to humans, underscoring its fundamental importance in proliferation control. Recent studies emphasize its non-canonical roles, such as in and neuronal function, but its primary legacy remains as a "guardian" of mitotic fidelity, counterbalanced by other ligases like SCF complexes to prevent errors in chromosome segregation.

Overview and Discovery

Definition and Biological Significance

The anaphase-promoting complex/cyclosome (APC/C) is a large multi-subunit ubiquitin-protein complex, approximately 1.2 MDa in humans, that targets regulatory proteins for proteasomal degradation by catalyzing their ubiquitination. Composed of 13 core subunits in mammals, APC/C assembles into a macromolecular machine that requires co-activators for full functionality and operates in a cell cycle-dependent manner to ensure ordered progression through division. This ubiquitin activity is essential for marking substrates with K11- or K48-linked chains, directing them to the 26S for timely breakdown. APC/C serves as a central regulator of , enabling the metaphase-to-anaphase transition by promoting sister chromatid separation and mitotic exit through targeted degradation of key inhibitors and cyclins. It also orchestrates the by suppressing premature S-phase entry, thereby preventing unscheduled . Beyond these core roles, APC/C governs to support , modulates the DNA damage response by stabilizing repair factors, and influences non-proliferative processes such as neuronal differentiation—where it controls post-mitotic morphogenesis—and cellular aging by maintaining genomic stability and . Evolutionarily conserved from to humans, APC/C underscores its indispensable role in eukaryotic cellular . Dysregulation of APC/C, often through subunit mutations or altered co-activator binding, disrupts ubiquitin-mediated , leading to —a driver of cancer—and neurodegeneration via aberrant protein accumulation in neurons.

Historical Identification

The discovery of the anaphase-promoting complex (APC/C) emerged from studies on the ubiquitin-mediated degradation of mitotic in the early . Seminal work by Surana et al. demonstrated that in budding , destruction of the CDC28/CLB mitotic , while essential for mitotic exit, is not strictly required for the metaphase-to- transition, highlighting the need for a regulated proteolytic system to initiate . This set the stage for identifying the key enzymatic machinery. In , parallel breakthroughs in metazoan systems revealed the complex's core function as a cell cycle-regulated . In oocyte extracts, Sudakin et al. isolated a large ~1.5 MDa complex, termed the cyclosome, exhibiting cyclin-selective E3 activity that targets for destruction at exit. Concurrently, in egg extracts, King et al. purified a 20S particle containing homologs of CDC16 and CDC27 proteins, which specifically ubiquitinates in a -dependent manner, establishing its role in onset. In budding , genetic screens for metaphase-arrest mutants had earlier identified CDC16, CDC23, and CDC27 as essential for sister chromatid separation, but their biochemical function remained unclear until 1995. Irniger et al. showed that these genes encode components required for B-type cyclin via the pathway, directly linking them to the cyclosome-like activity observed in extracts and unifying the yeast and metazoan discoveries as a conserved APC. Between 1996 and 2000, further isolation of core subunits, such as APC1, confirmed the complex's multisubunit nature and its conservation across eukaryotes, with early biochemical assays delineating its dependence on E1, E2 enzymes like Ubc4, and cell cycle-specific activation. These milestones solidified the APC as the primary E3 driving by degrading securin and cyclins. The nomenclature evolved to reflect these convergent findings: "cyclosome" for the metazoan versions emphasizing its cyclic regulation of levels, while "anaphase-promoting complex" () arose from highlighting its role in promoting . By the early , the terms unified as APC/C, and detailed characterization confirmed its identity as a cullin-RING ligase, with the discovery of the RING domain-containing subunit APC11 enabling chain assembly on substrates. Structural investigations in the , using negative-stain electron microscopy, first visualized the APC/C's large, wedge-shaped architecture, revealing a modular assembly akin to the cyclosome and subcomplexes involving TPR-repeat subunits like CDC16, CDC23, and CDC27. Advancing into the , cryo-EM technologies enabled near-atomic resolution structures, such as the 3.6 Å map of human APC/C bound to co-activators, elucidating subunit arrangements and catalytic core dynamics. These studies illuminated how and co-activators like CDC20 integrate into the complex's architecture to regulate activity. A recent milestone came in 2024, when cryo-EM structures of human apo-APC/C and the APC/C^{CDH1}:EMI1 complex at 3.0 Å and 2.9 Å resolution, respectively, revealed autoinhibitory mechanisms and how the EMI1 inhibitor binds to block substrate access, providing new insights into regulation.

Structural Organization

Subunit Composition

The anaphase-promoting complex (APC/C) is a multi-subunit E3 ubiquitin ligase consisting of 13 core subunits in budding () and 14 in s, with the human complex featuring an additional vertebrate-specific subunit, APC7. The core subunits are highly conserved across eukaryotes, with yeast orthologs including Apc1 (), Apc2 (cullin-like), Apc4 (platform), Apc5 (platform), Cdc16 (Apc6, TPR-lobe), Cdc23 (Apc8, TPR-lobe), Cdc27 (Apc3, TPR-lobe), Doc1 (Apc10, accessory), Apc11 (RING), Swm1 (Apc13, accessory), Mnd2 (Apc15, accessory), Apc9 (precursor to human Apc16), and Cdc26 (Apc12, TPR-stabilizing). In humans, the subunits are designated as APC1, APC2, APC3 (CDC27), APC4, APC5, APC6 (CDC16), APC7, APC8 (CDC23), APC10 (DOC1), APC11, APC12, APC13, APC15, and APC16, maintaining similar and orthology to yeast except for the added APC7. These subunits can be grouped into functional categories based on their structural and biochemical roles. The TPR-lobe is formed by the TPR-containing scaffold subunits APC3/CDC27, APC6/CDC16, APC8/CDC23, and APC7 (in humans), a large assembly of tetratricopeptide repeat (TPR) motifs that provides structural rigidity and serves as a docking platform for co-activators such as CDC20. APC1 acts as a key scaffold subunit linking the platform to the TPR-lobe. The catalytic core comprises APC2, a cullin-like subunit, and APC11, which contains a RING domain essential for recruiting E2 ubiquitin-conjugating enzymes. The platform substructure is built by APC4 and APC5, which bridge the catalytic core to the TPR-lobe and contribute to overall complex stability.
Functional GroupSubunits (Human/Yeast Orthologs)Key Features
Scaffold (TPR-lobe)APC3/CDC27/Cdc27, APC6/CDC16/Cdc16, APC8/CDC23/Cdc23, APC7 (human only)TPR motifs for dimerization and co-activator binding; forms outer shell.
Scaffold (Linker)APC1/Apc1Connects platform to TPR-lobe; contains and PC domains.
Catalytic CoreAPC2/Apc2, APC11/Apc11APC2: cullin homology with winged-helix domain; APC11: RING finger for E2 interaction.
PlatformAPC4/Apc4, APC5/Apc5APC4: β-propeller; APC5: TPR superhelix; links modules.
The APC/C assembles with a stoichiometry of one copy per distinct subunit type in most cases, though TPR-lobe components such as APC3, APC6, and APC8 incorporate two copies each to form homo-dimers, resulting in a total molecular mass of approximately 1.2 MDa and a roughly triangular shape with dimensions of about 20 nm. Accessory subunits like APC10 (Doc1) play a critical role in substrate recruitment by enhancing recognition of destruction motifs, while APC13 (Swm1) contributes to complex stability by bridging TPR subunits and preventing disassembly. APC15 (Mnd2) exhibits some variability in occupancy and helps regulate auto-ubiquitination of co-activators, though its precise stoichiometry can fluctuate.

Architectural Features

The anaphase-promoting complex/cyclosome (APC/C) is a large multi-subunit assembly with a triangular overall , featuring a central cavity, a peripheral TPR lobe, and three main structural elements: a platform, a catalytic core, and the TPR lobe. The complex has a of approximately 1.2 MDa and has been resolved by cryo-electron microscopy (cryo-EM) at resolutions of 3–4 Å in earlier studies and as high as 2.9 Å in recent structures of human APC/C. This hollow, wedge-like form provides a scaffold for subunit interactions and conformational flexibility essential to its role in regulation. Key structural domains define the APC/C's modular organization. The TPR lobe contains multiple tetratricopeptide repeat (TPR) domains that form an elongated scaffold capped by an APC7 homodimer. The catalytic core includes the RING domain of APC11, which protrudes from the APC2 subunit to facilitate assembly of the ligase module. Additionally, APC2 features a coiled-coil region and a zinc-binding module that contribute to and positioning of the catalytic elements. These domains, along with contributions from other subunits to the platform and TPR lobe, enable the complex's robust architecture. APC/C exhibits dynamic conformational states that toggle between inactive and active forms. The apo-APC/C adopts a closed conformation, with the catalytic module positioned adjacent to the APC4–APC5 heterodimer, as resolved at 3.2 Å by cryo-EM. In contrast, co-activator binding induces an open state, displacing the catalytic module upward to expose functional sites, as seen in the APC/C^{CDH1}:EMI1 complex at 2.9 Å resolution. EMI1 binding stabilizes an inhibited closed-like state by engaging multiple interfaces, including steric occlusion within the central cavity. These transitions highlight the complex's through rigid-body movements of its modules. The core architecture of APC/C is highly conserved across species, with striking similarities between and forms in the arrangement of the platform, catalytic core, and TPR lobe. However, APC/C includes species-specific features, such as the subunit APC16, which forms an extended α-helix along the TPR lobe and is absent in yeast, enhancing metazoan-specific stability and assembly.

Biochemical Mechanism

Ubiquitin Ligase Activity

The anaphase-promoting complex (APC/C) functions as a multi-subunit , which catalyzes the attachment of molecules to target proteins, thereby marking them for degradation by the 26S . In this process, APC/C recruits E2 -conjugating , such as UBE2C (also known as UBCH10), to facilitate the transfer of activated from the E2 to specific residues on substrate proteins. This results in the formation of polyubiquitin chains, predominantly linked through 11 (K11) residues, which serve as a degradation signal recognized by the . At the heart of APC/C's catalytic activity is the dyad formed by the (D cullin and COM domain) of and the RING domain of APC11. The domain, particularly its winged-helix B , binds to the E2~ conjugate, positioning it for activation, while the APC11 RING domain interacts directly with the E2 enzyme to promote the nucleophilic attack that discharges the bond. This catalytic core enables efficient transfer without requiring at the APC/C step, as the energy is provided by the pre-activated E2~ intermediate. The ubiquitination process proceeds through distinct steps: first, the substrate binds to APC/C, often exemplified by key targets like ; next, the E2 enzyme is recruited to the RING domain of APC11; and finally, is transferred to a substrate , with subsequent elongation of K11-linked chains facilitated by additional E2 enzymes such as UBE2S. This stepwise mechanism ensures precise chain assembly, with initial priming by UBE2C followed by extension for robust polyubiquitination. APC/C's ligase activity exhibits high processivity, allowing the addition of multiple molecules during a single enzyme-substrate encounter, which enhances efficiency and minimizes substrate dissociation. This processivity is further augmented by the dependence on co-activators, such as CDC20, which induce conformational changes in APC/C to optimize the catalytic core for transfer.

Substrate Recognition Motifs

The anaphase-promoting complex (APC/C) selectively targets substrates for ubiquitination through short linear sequence motifs, collectively known as degrons, which are embedded in the substrate proteins. These motifs include the destruction box (D-box), KEN-box, ABBA motif, and, in some cases, the O-box, enabling precise temporal regulation of protein degradation during progression. The primary motifs ensure specificity by interacting with co-activators and core APC/C components, preventing indiscriminate ubiquitination. The D-box, first identified in mitotic cyclins and later confirmed as a key APC/C degron, features the RxxLxxxxN/dΦ (where x is any , Φ is a hydrophobic residue such as or , and N/d is or aspartate). This motif binds directly to the β-propeller domains of co-activators CDC20 or CDH1, positioning the substrate for ubiquitination. The APC10 subunit (known as Doc1 in ) of the APC/C core enhances D-box affinity by providing a secondary , stabilizing the substrate-co-activator interaction and promoting efficient recognition. In securin, the D-box is essential for its APC/CCDC20-mediated degradation, which triggers sister separation at the metaphase-to-anaphase transition. The KEN-box, with the consensus sequence KENxxx, functions as a distinct that is particularly effective for APC/CCDH1 substrates, binding to a surface pocket on the co-activator's domain. Unlike the D-box, the KEN-box often works in combination with other motifs to fine-tune degradation timing. For instance, contains both a D-box and a KEN-box, allowing coordinated ubiquitination by APC/CCDC20 and APC/CCDH1 for complete mitotic exit. Geminin, an inhibitor of licensing, relies on its KEN-box for APC/CCDH1-dependent degradation, ensuring its absence during G1/ to permit replication initiation. The motif, characterized by the consensus [ILVF]x[ILMVP][FHY]x[DE] (where brackets denote possible residues), binds to a hydrophobic groove on the domain of CDC20, often competing with spindle assembly checkpoint proteins for co-activator access. This motif is found in substrates like A and BUBR1, contributing to early mitotic degradation events. The O-box, a less common D-box variant with sequences resembling RxxLΦ motifs but lacking strict N-terminal arginine, targets specific substrates such as ORC1 for APC/CCDH1-mediated destruction during G1, preventing premature . Substrate specificity arises from the combinatorial use of these motifs and differential affinities of co-activators: CDC20 favors canonical D-boxes for rapid targeting, while CDH1 recognizes a broader repertoire, including KEN-boxes and weaker D-box variants, to sustain degradation into G1. This dual system, reinforced by motif positioning and flanking sequences, establishes degradation hierarchies that align with .

Role in Cell Cycle Transitions

Metaphase to Anaphase Transition

The anaphase-promoting complex (APC/C), in association with its co-activator CDC20, becomes active at the stage of following satisfaction of the spindle assembly checkpoint (SAC), which ensures proper bipolar attachment of sister kinetochores to the mitotic spindle. This activation occurs in late or , marking a critical temporal switch that allows progression to . Prior to SAC satisfaction, unattached kinetochores generate a diffusible "wait-anaphase" signal, primarily through the formation of the mitotic checkpoint complex (MCC), which includes MAD2 and BubR1 (also known as MAD3 in ). The MCC binds to and inhibits CDC20, preventing its association with APC/C and thereby blocking ubiquitination of APC/C substrates until all chromosomes achieve proper alignment. Once kinetochores are aligned and the SAC is silenced, MCC disassembles, enabling APC/C^CDC20 to initiate substrate degradation. The primary substrate driving the metaphase-to-anaphase transition is securin, known as Pds1 in , which APC/C^CDC20 targets for polyubiquitination and subsequent proteasomal degradation via recognition of its destruction box (D-box) motif. Securin degradation liberates separase, an that cleaves the kleisin subunit of , the protein complex holding together; this cleavage allows the chromatids to segregate to opposite spindle poles, initiating . In addition to securin, APC/C^CDC20 promotes the early degradation of cyclin A during , independent of SAC status, contributing to the partial inactivation of (CDK1) and facilitating the overall transition.

Mitosis to G1 Transition

Following the metaphase-to-anaphase transition, the anaphase-promoting complex/cyclosome (APC/C) undergoes a critical switch from activation by its co-activator CDC20 to CDH1, which is essential for completing mitotic exit and entering the . This transition is initiated post-anaphase when APC/CCDC20 catalyzes the auto-ubiquitination and subsequent proteasomal degradation of CDC20 itself, thereby inactivating the APC/CCDC20 complex and allowing of CDH1 by protein phosphatase 2A (PP2A). As CDK1 activity declines due to partial degradation, the now-dephosphorylated CDH1 binds to APC/C in late or early G1, forming the active APC/CCDH1 complex that drives further progression through mitotic exit. A primary function of APC/CCDH1 during this phase is the targeted ubiquitination and degradation of , the regulatory subunit of CDK1, which fully inactivates CDK1 and permits key cellular reorganizations. The destruction of , which contains a recognition motif for APC/C, leads to the inactivation of CDK1 and thereby enables , spindle disassembly, and reformation of the . This process ensures the irreversible commitment to mitotic exit, as sustained CDK1 activity would otherwise block these post-mitotic events. In addition to cyclin B, APC/CCDH1 degrades other mitotic kinases such as Aurora B and Polo-like kinase 1 (), which are crucial for timely spindle disassembly and centralspindlin-mediated furrow ingression during . Aurora B degradation prevents persistent of midzone components, facilitating proper spindle elongation and chromosome decondensation, while destruction inactivates its role in maintaining spindle integrity, allowing full disassembly. These targeted proteolyses collectively coordinate the structural changes required for daughter cell separation. APC/CCDH1 activity persists throughout the , where it continues to suppress the accumulation of mitotic s like A and B, thereby preventing premature entry into and maintaining G1 quiescence. This sustained activity acts as a safeguard against unscheduled re-entry, ensuring genomic stability before initiates. Inactivation of APC/CCDH1 occurs later in G1 through CDK2-mediated of CDH1, which dissociates it from APC/C and permits progression to .

Functions in Other Cell Cycle Phases

In the G1/S transition, the anaphase-promoting complex/cyclosome (APC/C) associated with its co-activator Cdh1 (APC/CCdh1) plays a critical role in preparing cells for by targeting geminin for ubiquitin-mediated proteasomal degradation. Geminin normally binds and inhibits Cdt1, a key licensing factor that recruits the to origins of replication to form pre-replicative complexes (pre-RCs). By degrading geminin during late and G1, APC/CCdh1 relieves this inhibition, enabling Cdt1 to facilitate pre-RC assembly and licensing of replication origins for the upcoming . Prior to this, during the G0/G1 transition, APC/CCDH1 undergoes transient partial inactivation mediated by phosphorylation of CDH1 at Thr129, reducing its activity by approximately 33%. This allows accumulation of 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3 (PFKFB3), boosting to support metabolic demands for cell cycle entry. This activity persists through G1 until the onset of , when phosphorylation of Cdh1 by E-CDK2 inactivates APC/CCdh1, allowing accumulation of pro-S-phase factors. During , APC/C activity is generally suppressed to permit replication progression, but reactivation of APC/CCdh1 under conditions of replication stress helps prevent re-replication by targeting licensing factors and inhibiting new origin firing. For instance, in response to prolonged replication fork stalling, APC/CCdh1 degrades substrates such as Emi1 (an APC/C inhibitor) and certain origin recognition components, thereby limiting excessive origin activation and maintaining stability. Although primary degradation of factors like Treslin (also known as TICRR) occurs via the CRL4DTL to couple replication with progression, APC/C contributes indirectly by controlling CDK levels and ensuring timely inactivation of licensing pathways. This selective activity avoids re-licensing of origins during ongoing , a mechanism conserved across eukaryotes to enforce once-per-cycle replication. In , APC/C exhibits limited basal activity, primarily through APC/CCdc20 contributing to the early degradation of cyclin A to fine-tune CDK levels before . Cyclin A accumulates during but begins to decline in late G2/ via APC/CCdc20-dependent ubiquitination, preventing premature activation of mitotic CDKs and ensuring orderly G2/M progression. Additionally, in response to DNA damage during G2, Cdc14B phosphatase activates APC/CCdh1 by dephosphorylating Cdh1, leading to degradation of (). degradation stabilizes Claspin, a mediator of the ATR-Chk1 checkpoint pathway, thereby reinforcing the G2 arrest to allow and preventing genomic instability. This targeted thus supports checkpoint maintenance without broadly disrupting G2-specific functions. In , particularly during maturation, APC/C performs analogous roles to but with adaptations for the unique demands of , including extended APC/CCdc20 activity due to a less stringent spindle assembly checkpoint (SAC). In mammalian s, APC/CCdc20 initiates earlier than in somatic cells, driving timely degradation of securin and B1 to enable segregation in I while accommodating acentrosomal spindle formation. This prolonged Cdc20 association persists through I exit, suppressing B1 re-accumulation and facilitating the transition to II without an intervening . Such extended activity is essential for oocyte meiotic competence, as disruptions lead to segregation errors and , highlighting APC/C's conserved yet specialized contributions to meiotic fidelity.

Regulation of APC/C Activity

Co-activators

The anaphase-promoting complex/cyclosome (APC/C) requires co-activators for its activity, with CDC20 and CDH1 serving as the primary regulators that impart temporal specificity during the . These co-activators bind directly to the APC/C, enhancing substrate recruitment and enabling ubiquitination. CDC20 predominates in , while CDH1 functions in late through G1, ensuring ordered progression from to and subsequent mitotic exit. CDC20 associates with the APC/C during and , a process facilitated by of APC/C subunits, particularly in the TPR-lobe, by mitotic kinases like CDK1 and Plk1. This creates a high-affinity binding interface for CDC20's C-box motif with APC8 (also known as CDC23) and its IR-tail with APC3 (CDC27). Upon binding, CDC20 induces a conformational rearrangement in the APC/C catalytic core, positioning the E2 enzyme UbcH10 proximal to the RING domain of APC11 to initiate ubiquitination. The β-propeller domain of CDC20 specifically recognizes substrates via their destruction box (D-box) motifs, such as those in securin and , thereby driving the -to-anaphase transition. To limit its activity, CDC20 undergoes auto-ubiquitination, primarily in a Cdh1-dependent manner during late , leading to its proteasomal degradation and preventing premature activation of later substrates. In contrast, CDH1 binds the APC/C following mitotic exit, when CDK1 activity declines and phosphatase-mediated dephosphorylation relieves inhibitory modifications on CDH1 itself. This enables CDH1 to interact with the dephosphorylated APC/C in and G1, utilizing similar TPR-lobe sites as CDC20, including the C-box binding to APC8 and IR-tail to APC3, which likewise triggers a conformational opening of the catalytic site. CDH1 accommodates a broader substrate repertoire, recruiting proteins via both D-box and KEN-box motifs, such as cyclin A and Aurora kinases, to facilitate mitotic exit and maintain G1 stability. CDH1 activity persists until S-phase entry, when rising CDK activity rephosphorylates it, dissociating it from the APC/C and allowing progression to . This sequential handover from CDC20 to CDH1 ensures precise temporal control of APC/C-mediated degradation events.

Inhibitors and Checkpoints

The spindle assembly checkpoint (SAC) prevents premature activation of the during by ensuring all chromosomes are properly attached to the mitotic spindle before onset. Key SAC components, including Mad2, BubR1, and Bub3, assemble into the mitotic checkpoint complex (MCC), which binds to and sequesters the co-activator Cdc20, thereby inhibiting APC/C activity until bipolar spindle attachment is achieved. The MCC directly blocks substrate recruitment to APC/C by occupying binding sites and preventing Cdc20-mediated activation, maintaining this inhibition as long as unattached kinetochores generate the wait- signal. Beyond the SAC, additional inhibitors regulate APC/C in a cell cycle phase-specific manner to prevent untimely degradation of substrates. In mammalian cells, early mitotic inhibitor 1 (EMI1) binds APC/C-Cdh1 during S and , acting as a pseudosubstrate that mimics D-box motifs to competitively inhibit substrate binding at the APC/C D-box receptor site. EMI1 also engages multiple interaction sites on APC/C, including the KEN-box receptor and E2 enzyme docking regions, further suppressing ubiquitination. In budding yeast, Acm1 serves an analogous role as a pseudosubstrate inhibitor of APC/C-Cdh1, binding directly to Cdh1 and the APC/C core to block activity during . Similarly, in , Rca1 (regulator of cyclin A1) inhibits APC/C-Cdh1 (also known as Fzr) by binding to Cdh1 and preventing premature cyclin A degradation, ensuring proper progression through . Resolution of the SAC involves disassembly of the MCC to release Cdc20 and activate APC/C, enabling the metaphase-to-anaphase transition. The protein p31comet plays a central role in this process by binding Mad2 within the MCC, promoting ATP-dependent disassembly and extraction of Mad2, which destabilizes the complex and frees Cdc20. Phosphatases, particularly protein phosphatase 1 (PP1), contribute to checkpoint silencing by dephosphorylating key SAC components, such as Mad3/BubR1, which facilitates MCC instability and disassembly during mitotic slippage or normal progression. Recent structural studies using cryo-electron microscopy have revealed that EMI1 stabilizes the closed, inactive conformation of APC/C by engaging multiple sites, including the D-box co-receptor and E2-binding interfaces, thereby reinforcing inhibition until appropriate cell cycle cues.

Post-translational Modifications

The anaphase-promoting complex/cyclosome (APC/C) is subject to multiple post-translational modifications that dynamically regulate its activity throughout the . by (CDK1) plays a central role in activating the APC/C during . Specifically, CDK1, in complex with and the accessory protein Cks, phosphorylates key subunits such as APC3 (also known as Cdc27) at multiple sites within its tetratricopeptide repeat (TPR) loop domain and APC1 at sites in its corresponding loop region. These modifications create docking sites that enhance the binding affinity of the co-activator Cdc20 to the APC/C, thereby promoting its activity toward mitotic substrates. This coordinated is essential for timely activation in and , ensuring progression through . Recent structural analyses have further elucidated that the C-terminal disordered loop of APC8 (Apc8-L) undergoes conformational changes upon , unlocking the APC/C for co-activator binding and enhancing mitotic activation. In contrast, dephosphorylation of the APC/C by protein phosphatase 2A (PP2A) and protein phosphatase 1 (PP1) is critical for its reactivation in the . During mitotic exit, declining CDK1 activity allows PP2A-B56 and PP1 to remove inhibitory phosphates from APC/C subunits and the co-activator Cdh1, facilitating Cdh1 binding and sustaining APC/C activity to degrade G1/S-phase regulators. This event marks a key transition, preventing premature re-entry into the . Phosphorylation levels thus peak in to enable Cdc20-dependent activity, while reversal in and G1 supports Cdh1-mediated functions. Auto-ubiquitination represents another regulatory layer, where the APC/C targets its own co-activators for degradation once primary substrates are depleted. In late , APC/C^{Cdc20} promotes the ubiquitination of Cdc20 through an intramolecular (in cis) mechanism, independent of additional activators or the Doc1 subunit. This process limits Cdc20 accumulation, contributing to its oscillations and ensuring shutdown of APC/C^{Cdc20} activity post-anaphase to allow mitotic exit. Cdc20 levels thus rise in and peak in early before declining via this auto-ubiquitination. Sumoylation further fine-tunes APC/C function, primarily on the APC4 subunit at residues K772 and K798 in its C-terminal region. This modification, which is phosphorylation-dependent at nearby serines S777 and S779, peaks during and enhances the APC/C's activity toward specific substrates, such as the Hsl1 and the KIF18B. APC4 sumoylation promotes timely metaphase-to-anaphase progression and accurate chromosome segregation by increasing substrate binding and ubiquitination efficiency, with mutants lacking these sites causing mitotic delays and segregation errors. Recent work (as of 2025) has also revealed that mechanistic target of rapamycin () transiently inactivates APC/C during to boost , integrating metabolic signaling with regulation. Overall, these modifications collectively ensure precise temporal control of APC/C activity.

Broader Biological Roles and Implications

Non-mitotic Functions

Beyond its canonical roles in mitosis, the anaphase-promoting complex (APC/C), particularly when activated by Cdh1 (APC/CCdh1), exerts influence in post-mitotic neurons to regulate morphogenesis and survival. In neurons, APC/CCdh1 targets the inhibitor of differentiation protein Id2 for ubiquitin-mediated degradation in a D-box-dependent manner, thereby promoting axonal growth and overcoming inhibitory signals from myelin-associated molecules. Similarly, degradation of the transcription factor SnoN by APC/CCdh1 facilitates axon branching and layer-specific patterning in the cerebellar cortex. Inactivation of APC/CCdh1 through knockdown or mutation disrupts these processes, leading to excessive or aberrant axon growth and connectivity defects. Additionally, APC/CCdh1 degrades cyclin B1 to prevent aberrant cell cycle re-entry in post-mitotic neurons, ensuring long-term survival; loss of this activity triggers apoptosis. In DNA repair pathways, APC/CCdh1 modulates the response to double-strand breaks (DSBs) by controlling the stability of key repair factors. During , APC/CCdh1 degrades the E3 ligase RNF8, which otherwise ubiquitinates Ku80 for removal from DSB sites, thereby stabilizing the Ku70/80 heterodimer to facilitate (NHEJ) repair. This interaction promotes efficient Ku retention at breaks, enhancing NHEJ fidelity and termination. In the context of DNA damage checkpoints, APC/CCdh1 normally targets Claspin for degradation to terminate the G2/M checkpoint, but during active DNA damage, Claspin is protected from ubiquitination, allowing sustained ATR-Chk1 signaling to halt progression until repair completion. APC/CCdh1 also degrades CtIP to limit DNA end resection, favoring NHEJ over in G1. During meiosis and gametogenesis, APC/C exhibits prolonged activity tailored to the unique demands of oocyte maturation and chromosome segregation. In mammalian oocytes, APC/CCdh1 degrades Cdc20 in I to delay onset, ensuring proper alignment of homologous chromosomes before segregation. Between meiosis I and II, inhibitors like Emi2/Erp1 suppress APC/CCdc20 to prevent cyclin degradation and DNA re-replication, maintaining high levels for the second meiotic division. This extended APC/C regulation is critical for accurate homolog disjunction in meiosis I and sister chromatid separation in meiosis II, with disruptions leading to in gametes; in mouse oocytes, meiosis-specific modulation of APC/C activators like Cdh1 supports cytostatic factor (CSF) arrest until fertilization. Recent studies highlight APC/C's involvement in developmental processes through regulated substrate interactions. A 2022 investigation revealed that ID2 binds APC/C via its N-terminal region to core subunits and a C-terminal D-box to Cdh1, with CDK1 stabilizing ID2 during and enabling its degradation in G1. This dynamic interaction sustains G2/M progression while allowing ID2 turnover to reactivate basic helix-loop-helix transcription factors, influencing cell-type-specific during neuronal differentiation and broader developmental transitions.

Pathophysiological Relevance

Dysregulation of the anaphase-promoting complex/cyclosome (APC/C) plays a significant role in cancer , particularly through mutations that lead to overactive or impaired activity, resulting in genomic instability. For instance, loss-of-function mutations in subunits like ANAPC1, which encodes a scaffold component of APC/C, have been identified in colorectal and other cancers, disrupting proper chromosome segregation and promoting . Similarly, overexpression of APC11 has been associated with progression and poor prognosis by enhancing ubiquitination of specific substrates, promoting unchecked cell proliferation. In , hyperactive APC/C contributes to rapid progression, and its inhibition has been explored as a therapeutic strategy, with proteasome inhibitors like indirectly stabilizing APC/C substrates such as cyclins to induce mitotic arrest and . In neurodegenerative disorders, defects in APC/C-Cdh1 activity impair neuronal and survival. In , amyloid-beta (Aβ) oligomers trigger proteasome-dependent degradation of the co-activator Cdh1, leading to depletion of APC/C-Cdh1 and accumulation of substrates like glutaminase, which elevates glutamate levels and causes . This dysregulation also promotes re-entry in post-mitotic s, contributing to hyperphosphorylation and synaptic loss, as evidenced by models showing restored dendritic integrity upon APC/C-Cdh1 enhancement. In , APC/C interacts with the ligase Parkin, which modulates APC/C co-activators Cdc20 and Cdh1 to regulate mitotic proteins; mutations in Parkin disrupt this crosstalk, exacerbating dopaminergic loss and genomic instability. A 2022 review highlights APC/C as a key regulator of cellular aging through its control of , with mutations in APC/C subunits extending replicative lifespan by improving protein quality control and reducing aggregate accumulation. In , apc mutants exhibit enhanced via stabilized substrates that bolster stress resistance, suggesting conserved mechanisms in higher organisms where APC/C decline contributes to age-related proteotoxic decline. Therapeutically, APC/C modulation holds promise for disease intervention. In cancer, D-box peptide inhibitors developed in 2025 potently block APC/C-Cdc20 ubiquitination activity, surpassing small-molecule inhibitors like apcin and inducing mitotic arrest in tumor cells, as demonstrated in cellular assays. For neurodegeneration, enhancing APC/C-Cdh1 activity is proposed to restore substrate degradation and mitigate pathology, with recent 2025 studies expanding its roles in synaptic plasticity and axon guidance as potential targets. Recent advances include a 2024 cryo-EM structural comparison of APC/C from S. cerevisiae and humans, revealing conserved mechanisms with species-specific regulatory differences that inform therapeutic design for both proliferative and degenerative diseases.

References

  1. https://www.nature.com/articles/s41418-020-00648-0
  2. https://www.cell.com/current-biology/fulltext/S0960-9822(04)00696-7
  3. https://www.sciencedirect.com/science/article/pii/S1097276502005403
  4. https://pmc.ncbi.nlm.nih.gov/articles/PMC4456660/
  5. https://celldiv.biomedcentral.com/articles/10.1186/s13008-016-0021-6
  6. https://www.aging-us.com/article/103792/text
  7. https://pmc.ncbi.nlm.nih.gov/articles/PMC5454969/
  8. https://pubmed.ncbi.nlm.nih.gov/7787245/
  9. https://pubmed.ncbi.nlm.nih.gov/7736579/
  10. https://www.nature.com/articles/s41467-024-54398-5
  11. https://royalsocietypublishing.org/doi/10.1098/rsob.170204
  12. https://elifesciences.org/reviewed-preprints/100821
  13. https://www.pnas.org/doi/10.1073/pnas.1911388116
  14. https://www.nature.com/articles/nsmb.2593
  15. https://elifesciences.org/articles/100821
  16. https://pmc.ncbi.nlm.nih.gov/articles/PMC2864710/
  17. https://doi.org/10.1016/j.cell.2008.04.012
  18. https://doi.org/10.1016/j.molcel.2016.09.006
  19. https://genesdev.cshlp.org/content/15/18/2396.full
  20. https://genesdev.cshlp.org/content/14/6/655
  21. https://doi.org/10.1101/gad.1361905
  22. https://doi.org/10.1186/s13008-019-0057-5
  23. https://rupress.org/jcb/article/207/1/23/37866/Multiple-mechanisms-determine-the-order-of-APC-C
  24. https://doi.org/10.1083/jcb.200102093
  25. https://doi.org/10.1038/349132a0
  26. https://doi.org/10.1016/S1097-2765(00)80126-4
  27. https://pmc.ncbi.nlm.nih.gov/articles/PMC3430386/
  28. https://www.pnas.org/doi/10.1073/pnas.1604929113
  29. https://rupress.org/jcb/article/203/1/87/37472/Sequestration-of-CDH1-by-MAD2L2-prevents-premature
  30. https://www.cell.com/molecular-cell/pdf/S1097-2765%2807%2900375-9.pdf
  31. https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0159166
  32. https://www.nature.com/articles/s12276-018-0069-2
  33. https://www.sciencedirect.com/science/article/pii/S0960982208012931
  34. https://rupress.org/jcb/article/164/2/233/33526/Ordered-proteolysis-in-anaphase-inactivates-Plk1
  35. https://pmc.ncbi.nlm.nih.gov/articles/PMC2668763/
  36. https://rupress.org/jcb/article/154/1/85/32290/Activity-of-the-APCCdh1-form-of-the-anaphase
  37. https://celldiv.biomedcentral.com/articles/10.1186/1747-1028-4-2
  38. https://www.sciencedirect.com/science/article/pii/S0167488918304154
  39. https://pmc.ncbi.nlm.nih.gov/articles/PMC2428065/
  40. https://pmc.ncbi.nlm.nih.gov/articles/PMC3047751/
  41. https://pmc.ncbi.nlm.nih.gov/articles/PMC1810247/
  42. https://www.nature.com/articles/s41586-025-09328-w
  43. https://pmc.ncbi.nlm.nih.gov/articles/PMC4889930/
  44. https://pmc.ncbi.nlm.nih.gov/articles/PMC6211026/
  45. https://rupress.org/jcb/article/153/1/137/45927/Anaphase-Promoting-Complex-Cyclosome-Dependent
  46. https://pmc.ncbi.nlm.nih.gov/articles/PMC2591934/
  47. https://www.nature.com/articles/s41467-022-35461-5
  48. https://www.sciencedirect.com/science/article/pii/S096098220900685X
  49. https://rep.bioscientifica.com/view/journals/rep/146/2/R61.xml
  50. https://rupress.org/jcb/article/206/7/843/37873/Mastl-is-required-for-timely-activation-of-APC-C
  51. https://pmc.ncbi.nlm.nih.gov/articles/PMC6927175/
  52. https://www.molbiolcell.org/doi/10.1091/mbc.11.5.1555
  53. https://www.nature.com/articles/nature14471
  54. https://doi.org/10.1016/S0092-8674(00)81429-8
  55. https://celldiv.biomedcentral.com/articles/10.1186/1747-1028-5-23
  56. https://pubmed.ncbi.nlm.nih.gov/14593737/
  57. https://pubmed.ncbi.nlm.nih.gov/22193957/
  58. https://pubmed.ncbi.nlm.nih.gov/16921029/
  59. https://pubmed.ncbi.nlm.nih.gov/11751633/
  60. https://pubmed.ncbi.nlm.nih.gov/17030612/
  61. https://pubmed.ncbi.nlm.nih.gov/11782312/
  62. https://pubmed.ncbi.nlm.nih.gov/21300909/
  63. https://doi.org/10.1016/j.cub.2019.11.024
  64. https://pubmed.ncbi.nlm.nih.gov/39567505/
  65. https://doi.org/10.1016/j.celrep.2024.114290
  66. https://doi.org/10.1126/science.aad3925
  67. https://pmc.ncbi.nlm.nih.gov/articles/PMC6945068/
  68. https://www.molbiolcell.org/doi/10.1091/mbc.E20-04-0252
  69. https://doi.org/10.1016/j.cub.2011.09.051
  70. https://doi.org/10.1038/s41586-025-09328-w
  71. https://www.nature.com/articles/s41467-022-29502-2
  72. https://www.spandidos-publications.com/10.3892/ijmm.2020.4586
  73. https://www.mdpi.com/1422-0067/23/23/15327
  74. https://elifesciences.org/articles/104238
  75. https://www.lifescience.net/publications/1655141/new-functions-of-apcc-ubiquitin-ligase-in-the-nerv/
Add your contribution
Related Hubs
User Avatar
No comments yet.