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http://en.wikipedia.org/wiki/Anaphase-promoting_complex
Anaphase-promoting complex
From Wikipedia, the free encyclopedia
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 1113 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.[1] 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.
Contents
1 Function 2 APC/C Subunits 3 Substrate Recognition 4 Metaphase to Anaphase Transition 5 M to G1 Transition 6 Additional APC/C Regulation 7 References 8 Further reading 9 External links
Function
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 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 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.[2]
APC/C Subunits
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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.[3] 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 activators1. Apc10/Doc1, has been shown to promote substrate binding by mediating their interactions with Cdh1 and Cdc20.[4] 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.[5]
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 ubiquitinconjugating enzyme and the D-box rather than being an intermediate covalent carrier.[6] 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.[7] 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.[3] Although Cdc20 and Cdh1 may serve as D and KEN box receptors, the low affinity of these co-activator
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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.[3] 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 APCdoc1Cdh1, while addition of purified Doc1 to the APCdoc1Cdh1 construct restores the substrate binding ability.[4]
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.[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 Cdc20s 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
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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 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]
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. ISBN 0-9539181-2-2. 2. ^ Bruce Alberts, Alexander Johnson, Julian Lewis, Martin Raff, Keith Roberts, Peter Walter, ed. (2002). "Chapter 17. The Cell Cycle and Programmed Cell Death" (http://www.ncbi.nlm.nih.gov/books/NBK21056/). Molecular Biology of the Cell (http://www.ncbi.nlm.nih.gov/books/NBK21054/) (4th ed.). Garland Science. ISBN 0-8153-3218-1. 3. ^ a b c Barford, David (2011). "Structural insights into anaphase-promoting complex function and mechanism" (http://rstb.royalsocietypublishing.org/content/366/1584/3605.long#ref-46). Philosophical Transactions of the Royal Society B: Biological Sciences 366 (1584): 36053624. doi:10.1098/rstb.2011.0069 (http://dx.doi.org
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4.
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/10.1098%2Frstb.2011.0069). ^ a b Passmore, Lori A.; Elizabeth A. McCormack, Shannon W.N. Au, Angela Paul, Keith R. Willison, J. Wade Harper and David Barford (2003). "Doc1 mediates the activity of the anaphase-promoting complex by contributing to substrate recognition" (http://www.nature.com/emboj/journal/v22/n4/full/7594994a.html). The EMBO Journal 22 (4): 786796. doi:10.1093/emboj/cdg084 (http://dx.doi.org/10.1093%2Femboj%2Fcdg084). ^ Mansfeld, Jorg; Philippe Collin, Mark O. Collins, Jyoti S. Choudhary and Jonathon Pines (2011). "APC15 drives the turnover of MCC-CDC20 to make the spindle assembly checkpoint responsive to kinetochore attachment" (http://www.nature.com/ncb/journal/v13/n10/full/ncb2347.html). Nature Cell Biology 13 (10): 12341243. doi:10.1038/ncb2347 (http://dx.doi.org/10.1038%2Fncb2347). ^ King RW, Deshaies RJ, Peters JM, Kirschner MW. (1996). "How proteolysis drives the cell cycle". Science 274 (5293): 16529. doi:10.1126/science.274.5293.1652 (http://dx.doi.org/10.1126%2Fscience.274.5293.1652). PMID 8939846 (//www.ncbi.nlm.nih.gov/pubmed/8939846). ^ Kraft, Claudine; Hartmut C. Vodermaier1, , Sebastian Maurer-Stroh, Frank Eisenhaber, Jan-Michael Peters (2005). "The WD40 Propeller Domain of Cdh1 Functions as a Destruction Box Receptor for APC/C Substrates" (http://www.cell.com/molecular-cell/retrieve/pii/S1097276505012864). Molecular Cell 18 (5): 543553. doi:10.1016/j.molcel.2005.04.023 (http://dx.doi.org/10.1016%2Fj.molcel.2005.04.023). PMID 15916961 (//www.ncbi.nlm.nih.gov/pubmed/15916961). ^ 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" (http://www.ncbi.nlm.nih.gov/pubmed /11389834). Cell 105 (5): 645655. doi:10.1016/S0092-8674(01)00361-0 (http://dx.doi.org /10.1016%2FS0092-8674%2801%2900361-0). PMID 11389834 (//www.ncbi.nlm.nih.gov/pubmed/11389834). ^ Hansen, David; Alexander V. Loktev, Kenneth H. Ban, and Peter K. Jackson. "Plk1 Regulates Activation of the Anaphase Promoting Complex by Phosphorylating and Triggering SCFTrCP-dependent Destruction of the APC Inhibitor Emi1" (http://www.molbiolcell.org/content/15/12/5623.full). Molecular Biology of the Cell 15 (12): 56235634. doi:10.1091/mbc.E04-07-0598 (http://dx.doi.org/10.1091%2Fmbc.E04-07-0598). PMC 532041 (//www.ncbi.nlm.nih.gov/pmc/articles/PMC532041). PMID 15469984 (//www.ncbi.nlm.nih.gov/pubmed/15469984).
Further reading
Visintin R, Prinz S, Amon A (October 1997). "CDC20 and CDH1: a family of substrate-specific activators of APC-dependent proteolysis" (http://www.sciencemag.org/cgi/pmidlookup?view=long& pmid=9334304). Science 278 (5337): 4603. doi:10.1126/science.278.5337.460 (http://dx.doi.org /10.1126%2Fscience.278.5337.460). PMID 9334304 (//www.ncbi.nlm.nih.gov/pubmed/9334304). Hsu JY, Reimann JD, Srensen CS, Lukas J, Jackson PK (May 2002). "E2F-dependent accumulation of hEmi1 regulates S phase entry by inhibiting APCCdh1". Nat. Cell Biol. 4 (5): 35866. doi:10.1038/ncb785 (http://dx.doi.org/10.1038%2Fncb785). PMID 11988738 (//www.ncbi.nlm.nih.gov/pubmed/11988738). Zachariae W, Nasmyth K (August 1999). "Whose end is destruction: cell division and the anaphasepromoting complex" (http://www.genesdev.org/cgi/content/full/13/16/2039). Genes Dev. 13 (16): 203958. doi:10.1101/gad.13.16.2039 (http://dx.doi.org/10.1101%2Fgad.13.16.2039). PMID 10465783 (//www.ncbi.nlm.nih.gov/pubmed/10465783). (Review) Harper JW, Burton JL, Solomon MJ (September 2002). "The anaphase-promoting complex: it's not just for mitosis any more" (http://www.genesdev.org/cgi/content/full/16/17/2179). Genes Dev. 16 (17): 2179206. doi:10.1101/gad.1013102 (http://dx.doi.org/10.1101%2Fgad.1013102). PMID 12208841 (//www.ncbi.nlm.nih.gov/pubmed/12208841). (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 (2010 Nov 18). "Genomic evolution and complexity of the Anaphasepromoting Complex (APC) in land plants." (http://www.ncbi.nlm.nih.gov/pubmed/21087491). BMC plant
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External links
anaphase-promoting complex (http://www.nlm.nih.gov/cgi/mesh/2011/MB_cgi?mode=&term=anaphasepromoting+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) (http://www.pdbe.org/emsearch/anaphase%20promot*%20complex) Retrieved from "http://en.wikipedia.org/w/index.php?title=Anaphase-promoting_complex&oldid=545460744" Categories: Mitosis Proteins This page was last modified on 19 March 2013 at 16:33. Text is available under the Creative Commons Attribution-ShareAlike License; additional terms may apply. By using this site, you agree to the Terms of Use and Privacy Policy. Wikipedia is a registered trademark of the Wikimedia Foundation, Inc., a non-profit organization.
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