Difference between revisions of "Phosphatase Subfamily CDC14"

Revision as of 20:01, 15 September 2015

Phosphatase Classification: Fold CC1: Superfamily CC1: Family DSP: Subfamily CDC14

CDC14 subfamily consists of cell cycle genes widely found in eukaryotes with the exception of higher plants.

Evolution

CDC14 is found in most eukaryotes with the exception of higher plants. Most vertebrates express two paralogs typically designated CDC14A and CDC14B (see unpublished data from gOrtholog).

Domain

The CDC14 subfamily has two tandem structural equivalent domains linked by an alpha helix. Both domains have a DSP fold and only the second domain is catalytic active. CDC14 also has a conserved nuclear export sequence (NES) at C-terminal.

C. elegans cdc-14 has multiple isoforms and the longest one has a THAP domain at C-terminal. The THAP domain is a DNA-binding domain similar to P element transposase. However, the domain combination is dubious. The spliced ESTs show it is more probably the THAP domain belongs to another gene, by looking into UCSC Genome Browser.

Yeast CDC14 has a C-terminal sequence (517-551), which not only functions as a nuclear localization signal (NLS) in vivo but also binds to Kap121p (also known as Pse1p), an essential nuclear import carrier (karyopherin/importin) in yeast, in a Gsp1p-GTP-dependent manner in vitro [1]. In human, Kap121 (Pse1) ortholog can be found (IPO5), but human CDC14A and CDC14B have NLSs at N-terminal instead of C-terminal and it is unclear whether IPO5 binds to this region [2].

Function

Unlike the budding yeast enzyme, Cdc14 orthologs of most other species are not required for mitotic exit [3, 4]. In vertebrates, there are conflicting reports on the functions of the Cdc14 isoforms, but there is evidence for involvement in regulating mitotic entry, centrosome duplication, DNA repair, and cytokinesis [3, 4].

Human has two CDC14s, CDC14A and CDC14B. They have shown functional redundancy in double-strand breaks repair [5]. But, it is unclear whether they are functionally redundant in other bio processes.

Yeast CDC14

Cdc14 associated with Iqg1, dependent on several CHD-flanking Cdk sites, and efficiently dephosphorylated these sites in vitro. Iqg1, an IQGAP family member, is an essential protein in Saccharomyces cerevisiae required for assembly and contraction of the actomyosin ring. It has a calponin homology domain (CHD) that mediates the localization of F-actin to the ring which only occurs after anaphase [6].

References

1. Kobayashi J, Hirano H, and Matsuura Y. Crystal structure of the karyopherin Kap121p bound to the extreme C-terminus of the protein phosphatase Cdc14p. Biochem Biophys Res Commun. 2015 Jul 31;463(3):309-14. DOI:10.1016/j.bbrc.2015.05.060 | PubMed ID:26022122 | HubMed [Kobayashi15]
2. Gray CH, Good VM, Tonks NK, and Barford D. The structure of the cell cycle protein Cdc14 reveals a proline-directed protein phosphatase. EMBO J. 2003 Jul 15;22(14):3524-35. DOI:10.1093/emboj/cdg348 | PubMed ID:12853468 | HubMed [Gray03]
3. Mocciaro A and Schiebel E. Cdc14: a highly conserved family of phosphatases with non-conserved functions?. J Cell Sci. 2010 Sep 1;123(Pt 17):2867-76. DOI:10.1242/jcs.074815 | PubMed ID:20720150 | HubMed [Mocciaro10]
4. Bremmer SC, Hall H, Martinez JS, Eissler CL, Hinrichsen TH, Rossie S, Parker LL, Hall MC, and 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 | PubMed ID:22117071 | HubMed [Bremmer12]
5. Lin H, Ha K, Lu G, Fang X, Cheng R, Zuo Q, and Zhang P. Cdc14A and Cdc14B Redundantly Regulate DNA Double-Strand Break Repair. Mol Cell Biol. 2015 Nov;35(21):3657-68. DOI:10.1128/MCB.00233-15 | PubMed ID:26283732 | HubMed [Lin15]
6. Miller DP, Hall H, Chaparian R, Mara M, Mueller A, Hall MC, and Shannon KB. Dephosphorylation of Iqg1 by Cdc14 regulates cytokinesis in budding yeast. Mol Biol Cell. 2015 Aug 15;26(16):2913-26. DOI:10.1091/mbc.E14-12-1637 | PubMed ID:26085509 | HubMed [Miller15]