Anaphase-promoting complex

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Anaphase-promoting complex (APC) is a complex of several proteins which is activated during mitosis to initiate anaphase. The APC is an E3 ubiquitin ligase that marks target proteins for degradation by the 26S proteasome. The irreversibility of proteolysis is utilized by cells to give the cell cycle directionality.

The APC indirectly triggers the degradation of cohesin, the protein complex that binds sister chromatids together. During metaphase sister chromatids are linked by intact cohesin complexes. The spindle checkpoint inhibits the APC until all sister-kinetochores are attached to opposite poles of the mitotic spindle. When all kinetochores are properly attached the spindle checkpoint is silenced and the APC becomes active. The acitvated APC then targets securin for degradation. Securin inhibits a protease called separase, which cleaves cohesins allowing anaphase onset.

The APC also targets the mitotic cyclins for degradation, resulting in the inactivation of M-CdK (mitotic cyclin dependant kinase) complexes, promoting exit from mitosis.

There are two mitotic specificity factors for the APC, which target different sets of proteins and are regulated differently: Cdc20 and Cdh1.

Cdc20 binds to APC early in mitosis to activate it. It is not clear what kinases phosphorylate and activate the Cdc20-APC complex. It is known that M-Cdk is required for the activity of these kinases, although there is a significant delay between M-CdK activation and the activation of the Cdc20-APC complex. The molecular basis of the delay is unknown, but is believed to involve the key to the correct timing of anaphase initiation.<ref name=MBoC>{{ cite book

| year = 2002
| title = Molecular Biology of the Cell
| editor = Bruce Alberts, Alexander Johnson, Julian Lewis, Martin Raff, Keith Roberts, Peter Walter
| publisher = Garland Science
| chapter = Ch17
| edition = 4th

}}</ref>

Note that while activation of Cdc20-APC requires M-Cdk, the complex is also responsible for breaking the cylcin to deactivate M-CdK. CdK has an N-terminal destruction box (D-box). APC brings together E2 and the D-box rather than being an intermediate covalent carrier<ref>Template:Cite journal</ref>. Thus, as M-CdK and Cdc20-APC concentrations rise during the early part of mitosis, they are controlled by negative feedback.

Cdh1, is activated later to form a Cdh1-APC complex to drive exit from mitosis. M-CdK inhibits Hct1 by phosphorylation and therefore Hct1-APC only increases in late mitosis, after Cdc-APC has initiated destruction of M-cyclin.

It was the discovery of the APC (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 invoved 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 approach protein phosphorylation.

References

Zachariae, W. and K. Nasmyth (1999) Whose end is destruction: cell division and the anaphase-promoting complex. Genes Dev. 1999; 13(16): 2039-58 (Review)

J. Wade Harper, Janet L. Burton, and Mark J. Solomon (2002): The anaphase-promoting complex: it's not just for mitosis any more. Genes Dev. 2002; 16(17):2179-206 (Review)

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