| Structural highlights
6g84 is a 4 chain structure with sequence from Baker's yeast. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
| | Ligands: | , , |
| Gene: | CDC14, OAF3, YFR028C (Baker's yeast) |
| Activity: | Protein-tyrosine-phosphatase, with EC number 3.1.3.48 |
| Resources: | FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT |
Function
[CDC14_YEAST] Protein phosphatase which antagonizes mitotic cyclin-dependent kinase CDC28, the inactivation of which is essential for exit from mitosis. To access its substrates, is released from nucleolar sequestration during mitosis. Plays an essential in coordinating the nuclear division cycle with cytokinesis through the cytokinesis checkpoint. Involved in chromosome segregation, where it is required for meiosis I spindle dissambly as well as for establishing two consecutive chromosome segregation phases. Allows damaged actomyosin rings to be maintained to facilitate completion of cell division in response to minor perturbation of the cell division machinery. Inhibits transcription of ribosomal genes (rDNA) during anaphase and controls segregation of nucleolus by facilitating condensin targeting to rDNA chromatin in anaphase. Dephosphorylates SIC1, a CDC28 inhibitor, and SWI5, a transcription factor for SIC1, and induces degradation of mitotic cyclins, likely by dephosphorylating the activator of mitotic cyclin degradation, CDH1. Dephosphorylates the microtubule bundling factor ASE1 which is required to define a centered and focused mitotic spindle midzone that can drive continuous spindle elongation. Dephosphorylates the anaphase-promoting complex inhibitor ACM1, leading to its degradation. Facilitates INN1-CYK3 complex formation which promotes cytokinesis through the dephosphosprylation of CDC28-phosphosphorylated INN1. Reverts also the inhibitory CDC28 phosphorylation of CHS2 for endoplasmic reticulum export, ensuring that septum formation is contingent upon chromosome separation and exit from mitosis. Additional substrates for CDC14 are the formins BNI1 and BNR1, as well as CDC6, DBP2, DSN1, INCENP, KAR9, MCM3, ORC2, ORC6, SLD2, and SWI6. Activity is inhibited by interaction with NET1 which sequesters it to the nucleolus.[1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] [14] [15] [16] [17] [18] [19] [20] [21] [22] [23] [24] [25] [26] [27] [28] [29] [30]
Publication Abstract from PubMed
The cell division cycle consists of a series of temporally ordered events. Cell cycle kinases and phosphatases provide key regulatory input, but how the correct substrate phosphorylation and dephosphorylation timing is achieved is incompletely understood. Here we identify a PxL substrate recognition motif that instructs dephosphorylation by the budding yeast Cdc14 phosphatase during mitotic exit. The PxL motif was prevalent in Cdc14-binding peptides enriched in a phage display screen of native disordered protein regions. PxL motif removal from the Cdc14 substrate Cbk1 delays its dephosphorylation, whereas addition of the motif advances dephosphorylation of otherwise late Cdc14 substrates. Crystal structures of Cdc14 bound to three PxL motif substrate peptides provide a molecular explanation for PxL motif recognition on the phosphatase surface. Our results illustrate the sophistication of phosphatase-substrate interactions and identify them as an important determinant of ordered cell cycle progression.
A PxL motif promotes timely cell cycle substrate dephosphorylation by the Cdc14 phosphatase.,Kataria M, Mouilleron S, Seo MH, Corbi-Verge C, Kim PM, Uhlmann F Nat Struct Mol Biol. 2018 Nov 19. pii: 10.1038/s41594-018-0152-3. doi:, 10.1038/s41594-018-0152-3. PMID:30455435[31]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
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- ↑ Marston AL, Lee BH, Amon A. The Cdc14 phosphatase and the FEAR network control meiotic spindle disassembly and chromosome segregation. Dev Cell. 2003 May;4(5):711-26. PMID:12737806
- ↑ Geymonat M, Spanos A, Wells GP, Smerdon SJ, Sedgwick SG. Clb6/Cdc28 and Cdc14 regulate phosphorylation status and cellular localization of Swi6. Mol Cell Biol. 2004 Mar;24(6):2277-85. PMID:14993267
- ↑ Torres-Rosell J, Machin F, Jarmuz A, Aragon L. Nucleolar segregation lags behind the rest of the genome and requires Cdc14p activation by the FEAR network. Cell Cycle. 2004 Apr;3(4):496-502. Epub 2004 Apr 1. PMID:15004526
- ↑ D'Amours D, Stegmeier F, Amon A. Cdc14 and condensin control the dissolution of cohesin-independent chromosome linkages at repeated DNA. Cell. 2004 May 14;117(4):455-69. PMID:15137939
- ↑ Wang BD, Yong-Gonzalez V, Strunnikov AV. Cdc14p/FEAR pathway controls segregation of nucleolus in S. cerevisiae by facilitating condensin targeting to rDNA chromatin in anaphase. Cell Cycle. 2004 Jul;3(7):960-7. Epub 2004 Jul 4. PMID:15190202
- ↑ Bembenek J, Kang J, Kurischko C, Li B, Raab JR, Belanger KD, Luca FC, Yu H. Crm1-mediated nuclear export of Cdc14 is required for the completion of cytokinesis in budding yeast. Cell Cycle. 2005 Jul;4(7):961-71. Epub 2005 Jul 10. PMID:15917648
- ↑ Bloom J, Cross FR. Novel role for Cdc14 sequestration: Cdc14 dephosphorylates factors that promote DNA replication. Mol Cell Biol. 2007 Feb;27(3):842-53. Epub 2006 Nov 20. PMID:17116692 doi:http://dx.doi.org/10.1128/MCB.01069-06
- ↑ Khmelinskii A, Schiebel E. Assembling the spindle midzone in the right place at the right time. Cell Cycle. 2008 Feb 1;7(3):283-6. Epub 2007 Nov 21. PMID:18235228
- ↑ Hall MC, Jeong DE, Henderson JT, Choi E, Bremmer SC, Iliuk AB, Charbonneau H. Cdc28 and Cdc14 control stability of the anaphase-promoting complex inhibitor Acm1. J Biol Chem. 2008 Apr 18;283(16):10396-407. doi: 10.1074/jbc.M710011200. Epub, 2008 Feb 20. PMID:18287090 doi:http://dx.doi.org/10.1074/jbc.M710011200
- ↑ Geil C, Schwab M, Seufert W. A nucleolus-localized activator of Cdc14 phosphatase supports rDNA segregation in yeast mitosis. Curr Biol. 2008 Jul 8;18(13):1001-5. doi: 10.1016/j.cub.2008.06.025. PMID:18595708 doi:http://dx.doi.org/10.1016/j.cub.2008.06.025
- ↑ Clemente-Blanco A, Mayan-Santos M, Schneider DA, Machin F, Jarmuz A, Tschochner H, Aragon L. Cdc14 inhibits transcription by RNA polymerase I during anaphase. Nature. 2009 Mar 12;458(7235):219-22. doi: 10.1038/nature07652. Epub 2009 Jan 21. PMID:19158678 doi:http://dx.doi.org/10.1038/nature07652
- ↑ Chiroli E, Rancati G, Catusi I, Lucchini G, Piatti S. Cdc14 inhibition by the spindle assembly checkpoint prevents unscheduled centrosome separation in budding yeast. Mol Biol Cell. 2009 May;20(10):2626-37. doi: 10.1091/mbc.E08-11-1150. Epub 2009, Apr 1. PMID:19339280 doi:http://dx.doi.org/10.1091/mbc.E08-11-1150
- ↑ Mirchenko L, Uhlmann F. Sli15(INCENP) dephosphorylation prevents mitotic checkpoint reengagement due to loss of tension at anaphase onset. Curr Biol. 2010 Aug 10;20(15):1396-401. doi: 10.1016/j.cub.2010.06.023. Epub 2010, Jul 8. PMID:20619650 doi:http://dx.doi.org/10.1016/j.cub.2010.06.023
- ↑ Manzoni R, Montani F, Visintin C, Caudron F, Ciliberto A, Visintin R. Oscillations in Cdc14 release and sequestration reveal a circuit underlying mitotic exit. J Cell Biol. 2010 Jul 26;190(2):209-22. doi: 10.1083/jcb.201002026. PMID:20660629 doi:http://dx.doi.org/10.1083/jcb.201002026
- ↑ Akiyoshi B, Biggins S. Cdc14-dependent dephosphorylation of a kinetochore protein prior to anaphase in Saccharomyces cerevisiae. Genetics. 2010 Dec;186(4):1487-91. doi: 10.1534/genetics.110.123653. Epub 2010, Oct 5. PMID:20923974 doi:http://dx.doi.org/10.1534/genetics.110.123653
- ↑ Zhai Y, Yung PY, Huo L, Liang C. Cdc14p resets the competency of replication licensing by dephosphorylating multiple initiation proteins during mitotic exit in budding yeast. J Cell Sci. 2010 Nov 15;123(Pt 22):3933-43. doi: 10.1242/jcs.075366. Epub 2010, Oct 27. PMID:20980394 doi:http://dx.doi.org/10.1242/jcs.075366
- ↑ Bloom J, Cristea IM, Procko AL, Lubkov V, Chait BT, Snyder M, Cross FR. Global analysis of Cdc14 phosphatase reveals diverse roles in mitotic processes. J Biol Chem. 2011 Feb 18;286(7):5434-45. doi: 10.1074/jbc.M110.205054. Epub 2010 , Dec 2. PMID:21127052 doi:http://dx.doi.org/10.1074/jbc.M110.205054
- ↑ Bizzari F, Marston AL. Cdc55 coordinates spindle assembly and chromosome disjunction during meiosis. J Cell Biol. 2011 Jun 27;193(7):1213-28. doi: 10.1083/jcb.201103076. Epub 2011, Jun 20. PMID:21690308 doi:http://dx.doi.org/10.1083/jcb.201103076
- ↑ Tzeng YW, Huang JN, Schuyler SC, Wu CH, Juang YL. Functions of the mitotic B-type cyclins CLB1, CLB2, and CLB3 at mitotic exit antagonized by the CDC14 phosphatase. Fungal Genet Biol. 2011 Oct;48(10):966-78. doi: 10.1016/j.fgb.2011.07.001. Epub, 2011 Jul 19. PMID:21784165 doi:http://dx.doi.org/10.1016/j.fgb.2011.07.001
- ↑ Chin CF, Bennett AM, Ma WK, Hall MC, Yeong FM. Dependence of Chs2 ER export on dephosphorylation by cytoplasmic Cdc14 ensures that septum formation follows mitosis. Mol Biol Cell. 2012 Jan;23(1):45-58. doi: 10.1091/mbc.E11-05-0434. Epub 2011 Nov , 9. PMID:22072794 doi:http://dx.doi.org/10.1091/mbc.E11-05-0434
- ↑ Bouchoux C, Uhlmann F. A quantitative model for ordered Cdk substrate dephosphorylation during mitotic exit. Cell. 2011 Nov 11;147(4):803-14. doi: 10.1016/j.cell.2011.09.047. PMID:22078879 doi:http://dx.doi.org/10.1016/j.cell.2011.09.047
- ↑ Bremmer SC, Hall H, Martinez JS, Eissler CL, Hinrichsen TH, Rossie S, Parker LL, Hall MC, Charbonneau H. Cdc14 phosphatases preferentially dephosphorylate a subset of cyclin-dependent kinase (Cdk) sites containing phosphoserine. J Biol Chem. 2012 Jan 13;287(3):1662-9. doi: 10.1074/jbc.M111.281105. Epub 2011, Nov 23. PMID:22117071 doi:http://dx.doi.org/10.1074/jbc.M111.281105
- ↑ Quevedo O, Garcia-Luis J, Matos-Perdomo E, Aragon L, Machin F. Nondisjunction of a single chromosome leads to breakage and activation of DNA damage checkpoint in G2. PLoS Genet. 2012;8(2):e1002509. doi: 10.1371/journal.pgen.1002509. Epub 2012 Feb , 16. PMID:22363215 doi:http://dx.doi.org/10.1371/journal.pgen.1002509
- ↑ Palani S, Meitinger F, Boehm ME, Lehmann WD, Pereira G. Cdc14-dependent dephosphorylation of Inn1 contributes to Inn1-Cyk3 complex formation. J Cell Sci. 2012 Jul 1;125(Pt 13):3091-6. doi: 10.1242/jcs.106021. Epub 2012 Mar , 27. PMID:22454527 doi:http://dx.doi.org/10.1242/jcs.106021
- ↑ Sanchez-Diaz A, Nkosi PJ, Murray S, Labib K. The Mitotic Exit Network and Cdc14 phosphatase initiate cytokinesis by counteracting CDK phosphorylations and blocking polarised growth. EMBO J. 2012 Aug 29;31(17):3620-34. doi: 10.1038/emboj.2012.224. Epub 2012 Aug 7. PMID:22872148 doi:http://dx.doi.org/10.1038/emboj.2012.224
- ↑ Schild D, Byers B. Diploid spore formation and other meiotic effects of two cell-division-cycle mutations of Saccharomyces cerevisiae. Genetics. 1980 Dec;96(4):859-76. PMID:7021319
- ↑ Shirayama M, Matsui Y, Toh-e A. Dominant mutant alleles of yeast protein kinase gene CDC15 suppress the lte1 defect in termination of M phase and genetically interact with CDC14. Mol Gen Genet. 1996 May 23;251(2):176-85. PMID:8668128
- ↑ Taylor GS, Liu Y, Baskerville C, Charbonneau H. The activity of Cdc14p, an oligomeric dual specificity protein phosphatase from Saccharomyces cerevisiae, is required for cell cycle progression. J Biol Chem. 1997 Sep 19;272(38):24054-63. PMID:9295359
- ↑ Visintin R, Craig K, Hwang ES, Prinz S, Tyers M, Amon A. The phosphatase Cdc14 triggers mitotic exit by reversal of Cdk-dependent phosphorylation. Mol Cell. 1998 Dec;2(6):709-18. PMID:9885559
- ↑ Kataria M, Mouilleron S, Seo MH, Corbi-Verge C, Kim PM, Uhlmann F. A PxL motif promotes timely cell cycle substrate dephosphorylation by the Cdc14 phosphatase. Nat Struct Mol Biol. 2018 Nov 19. pii: 10.1038/s41594-018-0152-3. doi:, 10.1038/s41594-018-0152-3. PMID:30455435 doi:http://dx.doi.org/10.1038/s41594-018-0152-3
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