Biochimica et Biophysica Acta (BBA) - Protein Structure and Molecular Enzymology
ReviewStructure and function of the low Mr phosphotyrosine protein phosphatases
Section snippets
Overview
Formation and hydrolysis of phosphate esters are among the most important reactions carried out by cells. These reactions are involved in a lot of biochemical activities such as polymerisation and expression of genetic material, biological membrane functioning, interactions between macromolecules, signal transduction and substrate activation in many biosynthetic pathways. Formation and hydrolysis of phosphate monoesters in proteins, mostly at the serine, threonine (the only known phosphorylated
Occurrence
Low Mr PTPases (EC 3.1.3.48) were initially studied as low Mr soluble acid phosphatases (EC 3.1.3.2) due to their hydrolytic activity on phosphate esters and in particular on p-nitrophenylphosphate (pNPP). However, they are not inhibited by the classical inhibitors of either acid phosphatases (tartrate) or phosphoserine/threonine protein phosphatases (EDTA, fluoride, okadaic acid) 69, 70; instead, they are specifically inhibited by micromolar Zn2+ and vanadate, as well as by phenylarsine oxide
Biological activity
Similarly to the other PTPases, neither the true biological substrates of the low Mr PTPases are known nor the way they interact with other proteins in cells and their biological significance are well understood. Nevertheless, a number of data on this topic have been reported since 1989, when the efficient dephosphorylation in vitro of the autophosphorylated EGF receptor by the bovine liver IF2 was shown [99]; successively, this finding has been confirmed in brain in vivo [100]and the
Structure
At present, the genes or amino acid sequences of a number of low Mr PTPases are known, together with the three-dimensional structure of one of these proteins. Bovine liver IF2 was the first low Mr PTPase sequenced [115]. The protein consists of 157 amino acid residues (Mr 17 953), is N-acetylated and contains eight cysteines (all in the reduced form). The enzyme does not show any sequence homology with alkaline or acid phosphatases nor with the phosphothreonine/serine protein phosphatases. No
Substrate specificity and catalytic mechanism
Poor information is currently available on the substrate specificity and physiological substrates of the low Mr PTPases (as is also the case of most other PTPases). A number of studies have been carried out by the use of both dominant negative mutants and Tyr-phosphorylated synthetic peptides with sequences corresponding to those around phosphorylation sites of receptor and non-receptor proteins as model substrates. From these and other studies a number of possible physiological substrates and
Low Mr dual specificity PTPases
Dual specificity (ds) PTPases are an emerging class of enzymes able to hydrolyse both phosphotyrosine and phosphoserine/threonine residues in proteins, whose number is progressively increasing. Some dsPTPases display a reduced molecular mass, similar to that shown by the low Mr PTPases; all dsPTPases show sequence homology to each other but are structurally distinct from the low Mr PTPases, both groups sharing only the active site signature common to all PTPases and the catalytic mechanism. A
Concluding remarks
A group of tyrosine-specific and some dual specificity PTPases are characterised by reduced molecular masses; the latter enzymes are able to dephosphorylate substrates containing phosphotyrosine and phosphoserine/threonine residues in close proximity. Tyr-specific and ds low Mr PTPases share no sequence homology with each other outside the active site signature, though apparently acting with the same kinetic mechanism; this is also identical to that displayed by the other PTPase classes,
Acknowledgements
The authors thank Dr. N. Taddei for his skillful review of the manuscript. Work from our laboratory was supported, in part, by grants from Italian MURST (40% and 60%) CNR (Target Project on Biotechnology and Bioinstrumentation, Target Project on Peptidi Bioattivi and from the Italian Association for Cancer Research (AIRC).
References (179)
- et al.
J. Biol. Chem.
(1992) - et al.
Arch. Biochem. Biophys.
(1989) - et al.
J. Biol. Chem.
(1994) - et al.
J. Biol. Chem.
(1993) - et al.
J. Biol. Chem.
(1993) - et al.
J. Mol. Biol.
(1991) - et al.
J. Biol. Chem.
(1989) - et al.
FEBS Lett.
(1990) - et al.
J. Biol. Chem.
(1986) - et al.
J. Biol. Chem.
(1994)
Cell
Cell
Cell
Cell
Trends Biochem. Sci.
Trends Biochem. Sci.
Biochim. Biophys. Acta
Trends Biochem. Sci.
Cell
Cell
Cell
Cell
J. Biol. Chem.
J. Biol. Chem.
J. Biol. Chem.
J. Biol. Chem.
Trends Biochem. Sci.
Curr. Biol.
Cell
Trends Biochem. Sci.
Cell
Cell
Biochim. Biophys. Acta
Int. J. Biochem. Cell Biol.
J. Biol. Chem.
Arch. Biochem. Biophys.
Methods Enzymol.
Methods Enzymol.
Biochim. Biophys. Acta
Biochim. Biophys. Acta
Arch. Biochem. Biophys.
Arch. Biochem. Biophys.
Arch. Biochem. Biophys.
Biochim. Biophys. Acta
J. Biol. Chem.
J. Biol. Chem.
J. Biol. Chem.
J. Biol. Chem.
J. Biol. Chem.
J. Biol. Chem.
Cited by (101)
Alkoxide ligand controlled self-assembling of (imido)vanadium(V) compounds having a tetrahedral VO<inf>3</inf>N geometry
2020, Journal of Inorganic BiochemistryVibrio cholerae LMWPTP-2 display unique surface charge and grooves around the active site: Indicative of distinctive substrate specificity and scope to design specific inhibitor
2019, Biochimica et Biophysica Acta - Proteins and ProteomicsCitation Excerpt :Therefore, at physiological pH catalytic cysteine exists as thiolate (R-S−) ion and acts as nucleophile [51]. The catalytic mechanism of cysteine-dependent LMWPTPs, proceed in two distinct steps—SN2 displacement of tyrosine by the thiol (Cys12) that is followed by protonation of the tyrosinate through either Asp125 or a second conserved cysteine (Cys17) [4,52,53]. This creates an enzyme-bound thiophosphate ester intermediate and free tyrosine.
Low-molecular-weight protein tyrosine phosphatase expression as a prognostic factor for men with metastatic hormone-naïve prostate cancer
2017, Urologic Oncology: Seminars and Original InvestigationsVanadium-phosphatase complexes: Phosphatase inhibitors favor the trigonal bipyramidal transition state geometries
2015, Coordination Chemistry ReviewsCrystal structures of the apo form and a complex of human LMW-PTP with a phosphonic acid provide new evidence of a secondary site potentially related to the anchorage of natural substrates
2015, Bioorganic and Medicinal ChemistryCitation Excerpt :These modifications are catalyzed by protein kinases and phosphatases that modify serine, threonine or tyrosine residues on different proteins, receptors, transcription factors and binding proteins, thus controlling their biological functions. Tyrosine phosphorylation occurs to a much smaller extent than threonine/serine phosphorylation, but it plays a pivotal role in cellular signaling processes.2–5 The cellular level of the tyrosine phosphorylation is regulated by the opposing activity of protein tyrosine kinases (PTKs) and protein tyrosine phosphatases (PTPs).6
Crystal structure and putative substrate identification for the Entamoeba histolytica low molecular weight tyrosine phosphatase
2014, Molecular and Biochemical ParasitologyCitation Excerpt :Mammalian LMW-PTPs have been observed to be overexpressed in certain tumors, and thus are considered oncogenes [10]. The active site, or P-loop, of LMW-PTPs has the conserved sequence CLGNICR, conforming to the general PTP sequence CX5R [5,11]. The cysteine residue performs the nucleophilic attack on the phosphorus atom of the substrate phosphate group, producing a covalent phosphoenzyme intermediate [12,13].