Phosphatase Subfamily PGP

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Phosphatase Classification: Fold HAD: Superfamily HAD: Family NagD: Subfamily PGP

PGP is ubiquitous in eukaryotes and has been reported to act on both proteins and small molecules.

Evolution

PGP is found in most eukaryotes, typically in a single copy [1]. Vertebrates encode two members: PGP and PDXP.

Domain

PGPs have a single HAD-fold domain.

C. elegans PGP (K02D10.1) has at least three alternative splicing isoforms. One of the isoforms, supported by spliced ESTs, has a NIPSNAP domain at C-terminal (another two isoforms encode solely HAD and NIPSNAP domain, respectively). The domain combination is found in many other nematodes.

Functions

PDXP (Chronophin) is abundantly expressed in brain [2] (see also GTEx RNA-seq data). PDXP has two distinct substrates.

  • Pyridoxal 5'-phosphate. PDXP was first identified as pyridoxal phosphatase, which catalyzes the dephosphorylation of pyridoxal 5'-phosphate (PLP) and pyridoxine 5'-phosphate. PLP is the active form of vitamin B6 that acts as a coenzyme in maintaining biochemical homeostasis [2, 3, 4] and an important biomarker measures B6 status [5].
  • Cofilin. PDXP dephosphorylates cofilin at serine, regulating assembly and disassembly of actin filaments [6, 7, 8]. slingshot also dephosphorylates cofilin.

In contrast with PDXP, PGP (AUM) is widely expressed in different tissues (see also GTEx RNA-seq data). PGP is a putative tyrosine-specific phosphatase [9], but its physiological substrates are unknown. It also has a conserved phosphoglycolate phosphatase activity.

The yeast PGP, PHO13, has serine phosphatase activity against histone II-A and casein [10], and also acts on the synthetic small-molecule substrate PNPP (para-nitrophenyl phosphate). Deletion of PHO13 increases expression of pentose phosphate pathway genes and allows more efficient use of xylose.

References

  1. Chen MJ, Dixon JE, and Manning G. Genomics and evolution of protein phosphatases. Sci Signal. 2017 Apr 11;10(474). DOI:10.1126/scisignal.aag1796 | PubMed ID:28400531 | HubMed [Chen]
  2. Jang YM, Kim DW, Kang TC, Won MH, Baek NI, Moon BJ, Choi SY, and Kwon OS. Human pyridoxal phosphatase. Molecular cloning, functional expression, and tissue distribution. J Biol Chem. 2003 Dec 12;278(50):50040-6. DOI:10.1074/jbc.M309619200 | PubMed ID:14522954 | HubMed [Jang03]
  3. Gao G and Fonda ML. Identification of an essential cysteine residue in pyridoxal phosphatase from human erythrocytes. J Biol Chem. 1994 Mar 18;269(11):8234-9. PubMed ID:8132548 | HubMed [Gao94]
  4. Kim DW, Eum WS, Choi HS, Kim SY, An JJ, Lee SH, Sohn EJ, Hwang SI, Kwon OS, Kang TC, Won MH, Cho SW, Lee KS, Park J, and Choi SY. Human brain pyridoxal-5'-phosphate phosphatase: production and characterization of monoclonal antibodies. J Biochem Mol Biol. 2005 Nov 30;38(6):703-8. DOI:10.5483/bmbrep.2005.38.6.703 | PubMed ID:16336786 | HubMed [Kim05]
  5. Ueland PM, Ulvik A, Rios-Avila L, Midttun Ø, and Gregory JF. Direct and Functional Biomarkers of Vitamin B6 Status. Annu Rev Nutr. 2015;35:33-70. DOI:10.1146/annurev-nutr-071714-034330 | PubMed ID:25974692 | HubMed [Ueland15]
  6. Gohla A, Birkenfeld J, and Bokoch GM. Chronophin, a novel HAD-type serine protein phosphatase, regulates cofilin-dependent actin dynamics. Nat Cell Biol. 2005 Jan;7(1):21-9. DOI:10.1038/ncb1201 | PubMed ID:15580268 | HubMed [Gohla05]
  7. Huang TY, Minamide LS, Bamburg JR, and Bokoch GM. Chronophin mediates an ATP-sensing mechanism for cofilin dephosphorylation and neuronal cofilin-actin rod formation. Dev Cell. 2008 Nov;15(5):691-703. DOI:10.1016/j.devcel.2008.09.017 | PubMed ID:19000834 | HubMed [Huang08]
  8. Kestler C, Knobloch G, Tessmer I, Jeanclos E, Schindelin H, and Gohla A. Chronophin dimerization is required for proper positioning of its substrate specificity loop. J Biol Chem. 2014 Jan 31;289(5):3094-103. DOI:10.1074/jbc.M113.536482 | PubMed ID:24338687 | HubMed [Kestler14]
  9. Seifried A, Knobloch G, Duraphe PS, Segerer G, Manhard J, Schindelin H, Schultz J, and Gohla A. Evolutionary and structural analyses of mammalian haloacid dehalogenase-type phosphatases AUM and chronophin provide insight into the basis of their different substrate specificities. J Biol Chem. 2014 Feb 7;289(6):3416-31. DOI:10.1074/jbc.M113.503359 | PubMed ID:24338473 | HubMed [Seifried14]
  10. Tuleva B, Vasileva-Tonkova E, and Galabova D. A specific alkaline phosphatase from Saccharomyces cerevisiae with protein phosphatase activity. FEMS Microbiol Lett. 1998 Apr 1;161(1):139-44. DOI:10.1111/j.1574-6968.1998.tb12940.x | PubMed ID:9561742 | HubMed [Tuleva98]
All Medline abstracts: PubMed | HubMed