Phosphatase Subfamily CDC25

From PhosphataseWiki
Jump to: navigation, search

Phosphatase Classification: Fold CC3: Superfamily CC3: Family CDC25: Subfamily CDC25

Evolution

The CDC25 subfamily is found in most eukaryotes, but absent from most if not all of plants. It has multiple copies in many species, including three in human, two in Drosophila (string and twine) and four in C. elegans, all from apparently independent duplications.

Domain

Human CDC25s have an N-terminal regulatory domain known as M-phase inducer phosphatase domain and a C-terminal phosphatase domain with a rhodanese fold. Human CDC25s show alternative splicing of the regulatory domain. The N-terminal regulatory domain is classified as tetrapod-specific in Pfam, but has clearly conserved homology with CDC25 genes in Nematostella vectensis. A divergent N-terminal domain is also found in insects and Trichocephalida (an order of nematode), but not in Caenorhabditis species (see technical note of CDC25 N-terminal domain). Thus, the CDC25, N-terminal domain is probably lost in Caenorhabditis.

Catalytic activity and functions

Cdc25 dephosphorylates CDK kinases in many organisms, including yeasts, Drosophila and mammals, and so controls checkpoint progression of the cell cycle. CDC25 structures and functions have been reviewed in detail [1, 2, 3]. CDC25 removes inhibitory phosphates added by Wee1 from a threonine and a tyrosine in the G-loop of CDK1 and other CDKs, activating their cell cycle function. Duplicated CDC25s often have specific subfunctions: in Drosophila, string (stg) is involved in mitosis, and twine (twe) in meiosis (Interactive Fly ), while in mammals, CDC25A is involved in the G1-S checkpoint (dephosphorylating CDK2, CDK4 and CDK6) [4], and CDC25B and CDC25C are involved at G2-M.

Phosphatase domain structure

The three human CDC25s have the same structure, with a secondary structure (SS) combination of E1, H1, E2, H2, E3, E4, H3, E5, H4, E6, H5, E7. The strands E1, E2, E4, E5, E6 form a 5-stranded sheet; E3 and E7 form a 2-stranded sheet.

Human CDC25s and yeast YCH1 share the SS elements of E1, H1, E2, E3, E4, H3, E5, H4, E6, H5, E7. Yeast YCH1 structure differs from human CDC25s in two aspects:

  • While human CDC25s have an helix (H2) between E2 and E3, yeast YCH1 has an helix between E4 and H3, which we name H2-YCH1.
  • Yeast YCH1 has a helix between H4 and E6, which we name H4'-YCH1.

Note: These SS elements are the same as those reported in human CDC25 structures [5, 6], but differ from those reported for the YCH1 structure [7], where it had a SS elements of EHEEHHEHEH. Our assignments include annotations from DSSP and Stride and validated in structure visualization.

References

  1. Boutros R, Dozier C, and Ducommun B. The when and wheres of CDC25 phosphatases. Curr Opin Cell Biol. 2006 Apr;18(2):185-91. DOI:10.1016/j.ceb.2006.02.003 | PubMed ID:16488126 | HubMed [boutros06]
  2. Rudolph J. Cdc25 phosphatases: structure, specificity, and mechanism. Biochemistry. 2007 Mar 27;46(12):3595-604. DOI:10.1021/bi700026j | PubMed ID:17328562 | HubMed [rudolph07]
  3. Boutros R, Lobjois V, and Ducommun B. CDC25 phosphatases in cancer cells: key players? Good targets?. Nat Rev Cancer. 2007 Jul;7(7):495-507. DOI:10.1038/nrc2169 | PubMed ID:17568790 | HubMed [boutros07]
  4. Shen T and Huang S. The role of Cdc25A in the regulation of cell proliferation and apoptosis. Anticancer Agents Med Chem. 2012 Jul;12(6):631-9. PubMed ID:22263797 | HubMed [Shen]
  5. Fauman EB, Cogswell JP, Lovejoy B, Rocque WJ, Holmes W, Montana VG, Piwnica-Worms H, Rink MJ, and Saper MA. Crystal structure of the catalytic domain of the human cell cycle control phosphatase, Cdc25A. Cell. 1998 May 15;93(4):617-25. DOI:10.1016/s0092-8674(00)81190-3 | PubMed ID:9604936 | HubMed [Fauman98]
  6. Reynolds RA, Yem AW, Wolfe CL, Deibel MR Jr, Chidester CG, and Watenpaugh KD. Crystal structure of the catalytic subunit of Cdc25B required for G2/M phase transition of the cell cycle. J Mol Biol. 1999 Oct 29;293(3):559-68. DOI:10.1006/jmbi.1999.3168 | PubMed ID:10543950 | HubMed [Reynolds99]
  7. Yeo HK and Lee JY. Crystal structure of Saccharomyces cerevisiae Ygr203w, a homolog of single-domain rhodanese and Cdc25 phosphatase catalytic domain. Proteins. 2009 Aug 1;76(2):520-4. DOI:10.1002/prot.22420 | PubMed ID:19382206 | HubMed [Yeo09]
All Medline abstracts: PubMed | HubMed