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Anaphase-promoting complex

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Anaphase-promoting complex

This article refers to the cell-cycle regulatory complex, APC/C. For the tumor suppressor APC, in which mutations lead to colon cancer, see Adenomatous polyposis coli.

Anaphase-Promoting Complex (also called the cyclosome or APC/C) is an E3 [1]

It was the discovery of the APC/C (and SCF) and their key role 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.

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

Contents

  • Function 1
  • APC/C Subunits 2
  • Substrate Recognition 3
  • Metaphase to Anaphase Transition 4
  • M to G1 Transition 5
  • Additional APC/C Regulation 6
  • References 7
  • Further reading 8
  • External links 9

Function

The APC/C's main function is to trigger the transition from [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 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]

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 ubiquitylation of substrates when the C-terminal domain of Apc2 forms a tight complex with Apc11. In addition to the catalytic subunits, 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.[5]

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, Cdc27, 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.[6]

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.[7]

Substrate Recognition

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 [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.[9]

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.[5]

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.[5] 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.[6]

Metaphase to Anaphase Transition

As metaphase begins, the [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. [1]

This initiates a [1]

M to G1 Transition

Upon completion of mitosis, it is important that cells (except for embryonic ones) go through a growth period, known as [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 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 [1]

Additional APC/C Regulation

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 exracts 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.[10]

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 [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]

References

  1. ^ a b c d e f g h i j k l Morgan, David O. (2007). The Cell Cycle: Principles of Control. London: New Science Press.  
  2. ^ "Scientists map one of most important proteins in life – and cancer". The Institute of Cancer Research. 20 July 2014. Retrieved 22 July 2014. 
  3. ^ "Molecular architecture and mechanism of the anaphase-promoting complex". Nature. 20 July 2014. Retrieved 22 July 2014. 
  4. ^ Bruce Alberts, Alexander Johnson, Julian Lewis, Martin Raff, Keith Roberts, Peter Walter, ed. (2002). "Chapter 17. The Cell Cycle and Programmed Cell Death". Molecular Biology of the Cell (4th ed.). Garland Science.  
  5. ^ a b c Barford, David (2011). "Structural insights into anaphase-promoting complex function and mechanism". Philosophical Transactions of the Royal Society B: Biological Sciences 366 (1584): 3605–3624.  
  6. ^ a b Passmore, Lori A.; McCormack, Elizabeth A.; Au, Shannon W.N.; Paul, Angela; Willison, Keith R.; Harper, J. Wade; Barford, David (2003). "Doc1 mediates the activity of the anaphase-promoting complex by contributing to substrate recognition". The EMBO Journal 22 (4): 786–796.  
  7. ^ Mansfeld, Jorg; Collin, Philippe; Collins, Mark O.; Choudhary, Jyoti S.; Pines, Jonathon (2011). "APC15 drives the turnover of MCC-CDC20 to make the spindle assembly checkpoint responsive to kinetochore attachment". Nature Cell Biology 13 (10): 1234–1243.  
  8. ^ King RW, Deshaies RJ, Peters JM, Kirschner MW. (1996). "How proteolysis drives the cell cycle". Science 274 (5293): 1652–9.  
  9. ^ Kraft, Claudine; Vodermaier, Hartmut C.; Maurer-Stroh, Sebastian; Eisenhaber, Frank; Peters, Jan-Michael (2005). "The WD40 Propeller Domain of Cdh1 Functions as a Destruction Box Receptor for APC/C Substrates". Molecular Cell 18 (5): 543–553.  
  10. ^ JD, Reimann; Freed E; Hsu JY; Kramer ER; Peters JM; Jackson PK (2001). "Emi1 is a mitotic regulator that interacts with Cdc20 and inhibits the anaphase promoting complex". Cell 105 (5): 645–655.  
  11. ^ Hansen, David; Alexander V. Loktev; Kenneth H. Ban; Peter K. Jackson. "Plk1 Regulates Activation of the Anaphase Promoting Complex by Phosphorylating and Triggering SCFβTrCP-dependent Destruction of the APC Inhibitor Emi1". Molecular Biology of the Cell 15 (12): 5623–5634.  

Further reading

  • Visintin R, Prinz S, Amon A (October 1997). "CDC20 and CDH1: a family of substrate-specific activators of APC-dependent proteolysis". Science 278 (5337): 460–3.  
  • Hsu JY, Reimann JD, Sørensen CS, Lukas J, Jackson PK (May 2002). "E2F-dependent accumulation of hEmi1 regulates S phase entry by inhibiting APCCdh1". Nat. Cell Biol. 4 (5): 358–66.  
  • Zachariae W, Nasmyth K (August 1999). "Whose end is destruction: cell division and the anaphase-promoting complex". Genes Dev. 13 (16): 2039–58. ) Review ( 
  • Harper JW, Burton JL, Solomon MJ (September 2002). "The anaphase-promoting complex: it's not just for mitosis any more". Genes Dev. 16 (17): 2179–206. ) Review ( 
  • Lima Mde, F; Eloy, NB; Pegoraro, C; Sagit, R; Rojas, C; Bretz, T; Vargas, L; Elofsson, A; de Oliveira, AC; Hemerly, AS; Ferreira, PC (Nov 18, 2010). "Genomic evolution and complexity of the Anaphase-promoting Complex (APC) in land plants.". BMC plant biology 10: 254.  

External links

  • anaphase-promoting complex at the US National Library of Medicine Medical Subject Headings (MeSH)
  • 3D electron microscopy structures of Anaphase-promoting complex at the EM Data Bank(EMDB)
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