- Anaphase-promoting complex
Anaphase-Promoting Complex, also called cyclosome (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 still have unknown functions, but are highly conserved.
It was the discovery of the APC/C (and SCF) and the key role that they have in eukaryotic cell reproduction that established once and for all the importance of ubiquitin-mediated proteolysis in eukaryotic 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.
The APC/C's main function is to trigger the transition from metaphase to anaphase by tagging specific proteins for degradation. The two proteins of most importance that get degraded in this process as substrates of the APC/C are securin and S and M cyclins. Securin releases separase, a protease, after being degraded which in turn 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 separin, 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.
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 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.
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. 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. The APC/C probably has many substrate interaction sites, and while most of the APC/C's targets have at least one, if not both, of the aforementioned recognition sequences, they are not sufficient to instigate APC/C ubiquitination alone. 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.
Metaphase to Anaphase Transition
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.
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.
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.
M to G1 Transition
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.
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. 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.
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Cell cycle proteins Cyclin CDK CDK inhibitor P53 p63 p73 family Phases and
checkpointsOther cellular phases
Enzymes: CO CS and CN ligases (EC 6.1-6.3) 6.1: Carbon-OxygenAminoacyl tRNA synthetase (Tyrosine, Tryptophan, Threonine, Leucine, Isoleucine, Lysine, Alanine, Valine, Methionine, Serine, Aspartate, D-alanine-poly(phosphoribitol) ligase, Glycine, Proline, Cysteine, Glutamate, Glutamine, Arginine, Phenylalanine, Histidine, Asparagine, Aspartate, Glutamate, Lysine) 6.2: Carbon-Sulfur 6.3: Carbon-NitrogenGlutamine synthetase - Ubiquitin ligase (Cullin, Von Hippel-Lindau tumor suppressor, UBE3A, Mdm2, Anaphase-promoting complex, UBR1) - Glutathione synthetase - CTP synthase - Adenylosuccinate synthase - Argininosuccinate synthetase - Holocarboxylase synthetase - GMP synthase - Asparagine synthetase - Carbamoyl phosphate synthetase (I, II) - Gamma-glutamylcysteine synthetase Ligases: carbon-carbon ligases (EC 6.4) Biotin dependent carboxylase Other 6.5: Phosphoric Ester 6.6: Nitrogen-Metal
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