Protein Phosphatases

Abstract

Eukaryotic protein phosphatases are generally classified according to substrate specificity and three‐dimensional structure into two large groups: protein serine/threonine phosphatases, metalloproteins that dephosphorylate substrates via a single‐step reaction involving a metal‐activated water molecule, and protein tyrosine phosphatases, which contain an active‐site cysteine thiolate that forms a phosphoenzyme intermediate prior to nucleophilic breakdown by an activated water.

Keywords: phosphatase; phosphorylation; signalling; phosphoserine; phosphothreonine; phosphotyrosine

Figure 1.

Role of protein phosphatases in intracellular signalling. The phosphorylation state of proteins is regulated by kinases and phosphatases that respectively attach phosphate to or remove phosphate from specific residues in the context of short amino acid motifs. Phosphorylated amino acids serve as binding sites for noncatalytic domains (SH2, for example) of proteins that mediate downstream signalling through other distinct structures (grey boxes).

Figure 2.

Active‐site features and catalytic mechanisms of protein phosphatases. (a) Hydrogen‐bond coordination (dashed lines) of the active‐site residues, metal ions and water molecules (OH, W2, W3) in the serine/threonine phosphatase PP2B. (Adapted from Kissinger et al., ). Substrate phosphoryl groups are hydrolysed via a single‐step reaction involving a metal‐activated water molecule. (b) Model of the active site of Yersinia protein tyrosine phosphatase. (Adapted from Stuckey et al., ). A phosphoenzyme intermediate is formed by nucleophilic attack of the catalytic cysteine thiolate (Step 1) on substrate phosphotyrosine (pTyr), which is subsequently hydrolysed upon nucleophilic attack of an activated water molecule (Step 2). The catalytic arginine (Arg) hydrogen‐bonds with the equatorial oxygens of the substrate phosphoryl group to position it for attack and stabilize transition‐state intermediates.

close

References

Camps M, Nichols A, Gillieron C et al. (1998) Catalytic activation of the phosphatase MKP‐3 by ERK2 mitogen‐activated protein kinase. Science 280: 1262–1265.

Denu JM, Lohse DL, Vijayalakshmi J, Saper MA and Dixon JE (1996) Visualisation of intermediate and transition‐state structures in protein tyrosine phosphatase catalysis. Proceedings of the National Academy of Sciences of the USA 93: 2493–2498.

Egloff M‐P, Cohen PTW, Reinemer P and Barford D (1995) Crystal structure of the catalytic subunit of human protein phosphatase 1 and its complex with tungstate. Journal of Molecular Biology 254: 942–959.

Hubbard MJ and Cohen P (1993) On target with a new mechanism for the regulation of protein phosphorylation. Trends in Biochemical Sciences 18: 172–177.

Hunter T (2000) Signaling – 2000 and beyond. Cell 100: 113–127.

Jia Z, Barford D, Flint AJ and Tonks NK (1995) Structural basis for phosphotyrosine peptide recognition by protein tyrosine phosphatase 1B. Science 268: 1754–1758.

Kissinger CR, Parge HE, Knighton DR et al. (1995) Crystal structure of human calcineurin and the human FKBP12‐FK506‐calcineurin complex. Nature 378: 641–644.

Stuckey JA, Schubert HL, Fauman EB et al. (1994) Crystal structure of Yersinia protein tyrosine phosphatase at 2.5 Å and the complex with tungstate. Nature 370: 571–575.

Wishart MJ and Dixon JE (1998) Gathering STYX: phosphatase‐like form predicts functions for unique protein‐interaction domains. Trends in Biochemical Sciences 23: 301–306.

Wishart MJ and Dixon JE (2002) The archetype STYX/pseudo‐phosphatase complexes with a spermatid RNA binding protein and is essential for normal sperm production. Proceedings of the National Academy of Sciences of the USA 99: 2112–2117.

Further Reading

Ceulemans H, Stalmans W and Bollen M (2002) Regulator‐driven functional diversification of protein phosphatase‐1 in eukaryotic evolution. Bioessays 24: 371–381.

Barford D, Das AK and Egloff M‐P (1998) The structure and mechanism of protein phosphatases: insights into catalysis and regulation. Annual Reviews of Biophysics and Biomolecular Structure 27: 133–164.

Hunter T (1995) Protein kinases and phosphatases: the yin and yang of protein phosphorylation and signalling. Cell 80: 225–236.

Jackson MD and Denu JM (2001) Molecular reactions of protein phosphatases – insights from structure and chemistry. Chemical Reviews 101: 2313–2340.

Janssens V and Goris J (2001) Protein phosphatase 2A: a highly regulated family of serine/threonine phosphatases implicated in cell growth and signalling. Biochemical Journal 353: 417–439.

Majeti R and Weiss A (2001) Regulatory mechanisms for receptor protein tyrosine phosphatases. Chemical Reviews 101: 2441–2448.

Raugei G, Ramponi G and Chiarugi P (2002) Low molecular weight protein tyrosine phosphatases: small, but smart. Cellular and Molecular Life Sciences 59: 941–949.

Wishart MJ (2003) Styx/dead‐phosphatases. In: Bradshaw R and Dennis E (eds) Handbook of Cell Signaling. New York: Academic Press.

Zhan X‐L, Wishart MJ and Guan K‐L (2001) Nonreceptor tyrosine phosphatases in cellular signalling: regulation of mitogen‐activated protein kinases. Chemical Reviews 101: 2477–2496.

Contact Editor close
Submit a note to the editor about this article by filling in the form below.

* Required Field

How to Cite close
Wishart, Matthew J, and Guan, Kun‐Liang(May 2005) Protein Phosphatases. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1038/npg.els.0003472]