| Structural highlights
6mf6 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.
| | Gene: | CDC5, MSD2, PKX2, YMR001C, YM8270.03C (Baker's yeast), DBF4, DNA52, YDR052C, D4205, YD9609.07C (Baker's yeast) |
| Activity: | Polo kinase, with EC number 2.7.11.21 |
| Resources: | FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT |
Function
[CDC5_YEAST] Protein kinase required for the cell cycle where it is involved in mitotic exit. A component of the fear (CDC14 early anaphase release) network which promotes CDC14 release from the nucleolus during early anaphase. Phosphorylates SCC1/MCD1 and NET1.[1] [2] [3] [DBF4_YEAST] Regulatory subunit of the CDC7-DBF4 kinase, also called DBF4-dependent kinase (DDK), which is involved in cell cycle regulation of premitotic and premeiotic chromosome replication and in chromosome segregation. DDK plays an essential role in initiating DNA replication at replication origins by phosphorylating the MCM2 and MCM4 subunits of the MCM2-7 helicase complex. DBF4 recruits the catalytic subunit CDC7 to MCM2 and to origins of replication. DDK has also postreplicative functions in meiosis. DDK phosphorylates the meiosis-specific double-strand break protein MER2 for initiation of meiotic recombination. Interacts with CDC5 during meiosis to promote double-strand breaks and monopolar spindle orientation. Inhibits CDC5 activity during mitosis through direct binding to its PBD.[4] [5] [6] [7] [8] [9] [10] [11] [12] [13] [14] [15]
Publication Abstract from PubMed
Polo-like kinases (Plks) are key cell cycle regulators. They contain a kinase domain followed by a polo-box domain that recognizes phosphorylated substrates and enhances their phosphorylation. The regulatory subunit of the Dbf4-dependent kinase complex interacts with the polo-box domain of Cdc5 (the sole Plk in Saccharomyces cerevisiae) in a phosphorylation-independent manner. We have solved the crystal structures of the polo-box domain of Cdc5 on its own and in the presence of peptides derived from Dbf4 and a canonical phosphorylated substrate. The structure bound to the Dbf4-peptide reveals an additional density on the surface opposite to the phospho-peptide binding site that allowed us to propose a model for the interaction. We found that the two peptides can bind simultaneously and non-competitively to the polo-box domain in solution. Furthermore, point mutations on the surface opposite to the phosphopeptide binding site of the polo-box domain disrupt the interaction with the Dbf4 peptide in solution and cause an early anaphase arrest phenotype distinct from the mitotic exit defect typically observed in cdc5 mutants. Collectively, our data illustrates the importance of non-canonical interactions mediated by the polo-box domain and provide key mechanistic insights into the combinatorial recognition of substrates by Polo-like kinases.
Distinct surfaces on Cdc5/PLK Polo-box domain orchestrate combinatorial substrate recognition during cell division.,Almawi AW, Langlois-Lemay L, Boulton S, Rodriguez Gonzalez J, Melacini G, D'Amours D, Guarne A Sci Rep. 2020 Feb 25;10(1):3379. doi: 10.1038/s41598-020-60344-4. PMID:32099015[16]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Alexandru G, Uhlmann F, Mechtler K, Poupart MA, Nasmyth K. Phosphorylation of the cohesin subunit Scc1 by Polo/Cdc5 kinase regulates sister chromatid separation in yeast. Cell. 2001 May 18;105(4):459-72. PMID:11371343
- ↑ Stegmeier F, Visintin R, Amon A. Separase, polo kinase, the kinetochore protein Slk19, and Spo12 function in a network that controls Cdc14 localization during early anaphase. Cell. 2002 Jan 25;108(2):207-20. PMID:11832211
- ↑ Yoshida S, Toh-e A. Budding yeast Cdc5 phosphorylates Net1 and assists Cdc14 release from the nucleolus. Biochem Biophys Res Commun. 2002 Jun 14;294(3):687-91. doi:, 10.1016/S0006-291X(02)00544-2. PMID:12056824 doi:http://dx.doi.org/10.1016/S0006-291X(02)00544-2
- ↑ Dowell SJ, Romanowski P, Diffley JF. Interaction of Dbf4, the Cdc7 protein kinase regulatory subunit, with yeast replication origins in vivo. Science. 1994 Aug 26;265(5176):1243-6. PMID:8066465
- ↑ Duncker BP, Shimada K, Tsai-Pflugfelder M, Pasero P, Gasser SM. An N-terminal domain of Dbf4p mediates interaction with both origin recognition complex (ORC) and Rad53p and can deregulate late origin firing. Proc Natl Acad Sci U S A. 2002 Dec 10;99(25):16087-92. Epub 2002 Nov 19. PMID:12441400 doi:http://dx.doi.org/10.1073/pnas.252093999
- ↑ Valentin G, Schwob E, Della Seta F. Dual role of the Cdc7-regulatory protein Dbf4 during yeast meiosis. J Biol Chem. 2006 Feb 3;281(5):2828-34. Epub 2005 Nov 30. PMID:16319063 doi:http://dx.doi.org/10.1074/jbc.M510626200
- ↑ Sheu YJ, Stillman B. Cdc7-Dbf4 phosphorylates MCM proteins via a docking site-mediated mechanism to promote S phase progression. Mol Cell. 2006 Oct 6;24(1):101-13. PMID:17018296 doi:http://dx.doi.org/10.1016/j.molcel.2006.07.033
- ↑ Matos J, Lipp JJ, Bogdanova A, Guillot S, Okaz E, Junqueira M, Shevchenko A, Zachariae W. Dbf4-dependent CDC7 kinase links DNA replication to the segregation of homologous chromosomes in meiosis I. Cell. 2008 Nov 14;135(4):662-78. doi: 10.1016/j.cell.2008.10.026. PMID:19013276 doi:http://dx.doi.org/10.1016/j.cell.2008.10.026
- ↑ Wan L, Niu H, Futcher B, Zhang C, Shokat KM, Boulton SJ, Hollingsworth NM. Cdc28-Clb5 (CDK-S) and Cdc7-Dbf4 (DDK) collaborate to initiate meiotic recombination in yeast. Genes Dev. 2008 Feb 1;22(3):386-97. doi: 10.1101/gad.1626408. PMID:18245450 doi:http://dx.doi.org/10.1101/gad.1626408
- ↑ Bruck I, Kaplan D. Dbf4-Cdc7 phosphorylation of Mcm2 is required for cell growth. J Biol Chem. 2009 Oct 16;284(42):28823-31. doi: 10.1074/jbc.M109.039123. Epub, 2009 Aug 18. PMID:19692334 doi:http://dx.doi.org/10.1074/jbc.M109.039123
- ↑ Miller CT, Gabrielse C, Chen YC, Weinreich M. Cdc7p-Dbf4p regulates mitotic exit by inhibiting Polo kinase. PLoS Genet. 2009 May;5(5):e1000498. doi: 10.1371/journal.pgen.1000498. Epub 2009 , May 29. PMID:19478884 doi:http://dx.doi.org/10.1371/journal.pgen.1000498
- ↑ Jones DR, Prasad AA, Chan PK, Duncker BP. The Dbf4 motif C zinc finger promotes DNA replication and mediates resistance to genotoxic stress. Cell Cycle. 2010 May 15;9(10):2018-26. Epub 2010 May 15. PMID:20436286
- ↑ Chen YC, Weinreich M. Dbf4 regulates the Cdc5 Polo-like kinase through a distinct non-canonical binding interaction. J Biol Chem. 2010 Dec 31;285(53):41244-54. doi: 10.1074/jbc.M110.155242. Epub, 2010 Oct 29. PMID:21036905 doi:http://dx.doi.org/10.1074/jbc.M110.155242
- ↑ Kaplan DL, Bruck I. Methods to study kinase regulation of the replication fork helicase. Methods. 2010 Jul;51(3):358-62. doi: 10.1016/j.ymeth.2010.02.013. Epub 2010 Feb, 17. PMID:20170732 doi:http://dx.doi.org/10.1016/j.ymeth.2010.02.013
- ↑ Sheu YJ, Stillman B. The Dbf4-Cdc7 kinase promotes S phase by alleviating an inhibitory activity in Mcm4. Nature. 2010 Jan 7;463(7277):113-7. doi: 10.1038/nature08647. PMID:20054399 doi:http://dx.doi.org/10.1038/nature08647
- ↑ Almawi AW, Langlois-Lemay L, Boulton S, Rodriguez Gonzalez J, Melacini G, D'Amours D, Guarne A. Distinct surfaces on Cdc5/PLK Polo-box domain orchestrate combinatorial substrate recognition during cell division. Sci Rep. 2020 Feb 25;10(1):3379. doi: 10.1038/s41598-020-60344-4. PMID:32099015 doi:http://dx.doi.org/10.1038/s41598-020-60344-4
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