Taxonomic distribution of proteins containing PTPc_DSPc domains

The tree below includes only several representative species and genera. The complete taxonomic breakdown of all proteins containing PTPc_DSPc domains can be accessed here. Click the counts or percentage values to display the corresponding proteins.

Protein tyrosine phosphatases in the developing nervous system.

VanVactor D
Curr Opin Cell Biol. 1998; 10: 174-81

Protein tyrosine phosphatases (PTPs) constitute a diverse family of intracellular and transmembrane proteins. Expression data and recent genetic analyses indicate that many PTPs play important roles in different aspects of nervous system development. Although PTP mechanisms are still poorly understood, current data suggest considerable complexity in these signaling pathways.

Protein-tyrosine phosphatases: biological function, structural characteristics, and mechanism of catalysis.

Zhang ZY
Crit Rev Biochem Mol Biol. 1998; 33: 1-52

The protein-tyrosine phosphatases (PTPases) superfamily consists of tyrosine-specific phosphatases, dual specificity phosphatases, and the low-molecular-weight phosphatases. They are modulators of signal transduction pathways that regulate numerous cell functions. Malfunction of PTPases have been linked to a number of oncogenic and metabolic disease states, and PTPases are also employed by microbes and viruses for pathogenicity. There is little sequence similarity among the three subfamilies of phosphatases. Yet, three-dimensional structural data show that they share similar conserved structural elements, namely, the phosphate-binding loop encompassing the PTPase signature motif (H/V)C(X)5R(S/T) and an essential general acid/base Asp residue on a surface loop. Biochemical experiments demonstrate that phosphatases in the PTPase superfamily utilize a common mechanism for catalysis going through a covalent thiophosphate intermediate that involves the nucleophilic Cys residue in the PTPase signature motif. The transition states for phosphoenzyme intermediate formation and hydrolysis are dissociative in nature and are similar to those of the solution phosphate monoester reactions. One strategy used by these phosphatases for transition state stabilization is to neutralize the developing negative charge in the leaving group. A conformational change that is restricted to the movement of a flexible loop occurs during the catalytic cycle of the PTPases. However, the relationship between loop dynamics and enzyme catalysis remains to be established. The nature and identity of the rate-limiting step in the PTPase catalyzed reaction requires further investigation and may be dependent on the specific experimental conditions such as temperature, pH, buffer, and substrate used. In-depth kinetic and structural analysis of a representative number of phosphatases from each group of the PTPase superfamily will most likely continue to yield insightful mechanistic information that may be applicable to the rest of the family members.

Protein tyrosine phosphatases in signal transduction.

Neel BG, Tonks NK
Curr Opin Cell Biol. 1997; 9: 193-204

Protein-tyrosyl phosphorylation, regulated by protein tyrosine kinases and protein tyrosine phosphatases (PTPs), is a key cellular control mechanism. Until recently, little was known about PTPs. However, the past two years have witnessed an explosion of information about PTP structure, regulation and function. Crystal structures of several PTPs have provided insights into enzymatic mechanisms and regulation and suggested the design of 'substrate-trapping' mutants. Candidate homophilic and heterophilic ligands for transmembrane PTPs have been identified, and roles for transmembrane PTPs in regulating cell-cell interactions have been suggested. Finally, progress has been made in understanding signaling by Src homology 2 domain containing PTPs and PTPs controlling yeast osmoregulatory pathways.

An RNA 5'-triphosphatase related to the protein tyrosine phosphatases.

Takagi T, Moore CR, Diehn F, Buratowski S
Cell. 1997; 89: 867-73

mRNA capping requires the sequential action of three enzymatic activities: RNA triphosphatase, guanylyl-transferase, and methyltransferase. Here we characterize a gene (CEL-1) believed to encode the C. elegans capping enzyme. CEL-1 has a C-terminal domain containing motifs found in yeast and vaccinia virus capping enzyme guanylyltransferases. The N-terminal domain of CEL-1 has RNA triphosphatase activity. Surprisingly, this domain does not resemble the vaccinia virus capping enzyme but does have significant sequence similarity to the protein tyrosine phosphatase (PTP) enzyme family. However, CEL-1 has no detectable PTP activity. The mechanism of the RNA triphosphatase is similar to that of PTPs: the active site contains a conserved nucleophilic cysteine required for activity. These results broaden the superfamily of PTP-like phosphatases to include enzymes with RNA substrates.

Structure, mechanism, and specificity of protein-tyrosine phosphatases.

Zhang ZY
Curr Top Cell Regul. 1997; 35: 21-68

Structure and function of the protein tyrosine phosphatases.

Fauman EB, Saper MA
Trends Biochem Sci. 1996; 21: 413-7

The tyrosine and dual-specificity phosphatases are involved in signaling, cell growth and differentiation, and the cell cycle. The enzymes share a common catalytic mechanism mediated by an active site cysteine, arginine and aspartic acid. Supplementary domains assist in targeting and substrate specificity.

From form to function: signaling by protein tyrosine phosphatases.

Tonks NK, Neel BG
Cell. 1996; 87: 365-8

Crystal structure of the dual specificity protein phosphatase VHR.

Yuvaniyama J, Denu JM, Dixon JE, Saper MA
Science. 1996; 272: 1328-31

Dual specificity protein phosphatases (DSPs) regulate mitogenic signal transduction and control the cell cycle. Here, the crystal structure of a human DSP, vaccinia H1-related phosphatase (or VHR), was determined at 2.1 angstrom resolution. A shallow active site pocket in VHR allows for the hydrolysis of phosphorylated serine, threonine, or tyrosine protein residues, whereas the deeper active site of protein tyrosine phosphatases (PTPs) restricts substrate specificity to only phosphotyrosine. Positively charged crevices near the active site may explain the enzyme's preference for substrates with two phosphorylated residues. The VHR structure defines a conserved structural scaffold for both DSPs and PTPs. A "recognition region," connecting helix alpha1 to strand beta1, may determine differences in substrate specificity between VHR, the PTPs, and other DSPs.

Protein tyrosine phosphatases take off.

Barford D, Jia Z, Tonks NK
Nat Struct Biol. 1995; 2: 1043-53

Protein tyrosine phosphatases (PTPs) are a family of signal transduction enzymes that dephosphorylate phosphotyrosine containing proteins. Structural and kinetic studies provide a molecular understanding of how these enzymes regulate a wide range of intracellular processes.

Crystal structure of the catalytic subunit of human protein phosphatase 1 and its complex with tungstate.

Egloff MP, Cohen PT, Reinemer P, Barford D
J Mol Biol. 1995; 254: 942-59

Protein phosphatase 1 (PP1) is a serine/threonine protein phosphatase that is essential in regulating diverse cellular processes. Here we report the crystal structure of the catalytic subunit of human PP1 gamma 1 and its complex with tungstate at 2.5 A resolution. The anomalous scattering from tungstate was used in a multiple wavelength anomalous dispersion experiment to derive crystallographic phase information. The protein adopts a single domain with a novel fold, distinct from that of the protein tyrosine phosphatases. A di-nuclear ion centre consisting of Mn2+ and Fe2+ is situated at the catalytic site that binds the phosphate moiety of the substrate. Proton-induced X-ray emission spectroscopy was used to identify the nature of the ions bound to the enzyme. The structural data indicate that dephosphorylation is catalysed in a single step by a metal-activated water molecule. This contrasts with other phosphatases, including protein tyrosine phosphatases, acid and alkaline phosphatases which form phosphoryl-enzyme intermediates. The structure of PP1 provides insight into the molecular mechanism for substrate recognition, enzyme regulation and inhibition of this enzyme by toxins and tumour promoters and a basis for understanding the expanding family of related phosphatases which include PP2A and PP2B (calcineurin).

Structural basis for phosphotyrosine peptide recognition by protein tyrosine phosphatase 1B.

Jia Z, Barford D, Flint AJ, Tonks NK
Science. 1995; 268: 1754-8

The crystal structures of a cysteine-215-->serine mutant of protein tyrosine phosphatase 1B complexed with high-affinity peptide substrates corresponding to an autophosphorylation site of the epidermal growth factor receptor were determined. Peptide binding to the protein phosphatase was accompanied by a conformational change of a surface loop that created a phosphotyrosine recognition pocket and induced a catalytically competent form of the enzyme. The phosphotyrosine side chain is buried within the period and anchors the peptide substrate to its binding site. Hydrogen bonds between peptide main-chain atoms and the protein contribute to binding affinity, and specific interactions of acidic residues of the peptide with basic residues on the surface of the enzyme confer sequence specificity.

Crystal structure of human protein tyrosine phosphatase 1B.

Barford D, Flint AJ, Tonks NK
Science. 1994; 263: 1397-404

Protein tyrosine phosphatases (PTPs) constitute a family of receptor-like and cytoplasmic signal transducing enzymes that catalyze the dephosphorylation of phosphotyrosine residues and are characterized by homologous catalytic domains. The crystal structure of a representative member of this family, the 37-kilodalton form (residues 1 to 321) of PTP1B, has been determined at 2.8 A resolution. The enzyme consists of a single domain with the catalytic site located at the base of a shallow cleft. The phosphate recognition site is created from a loop that is located at the amino-terminus of an alpha helix. This site is formed from an 11-residue sequence motif that is diagnostic of PTPs and the dual specificity phosphatases, and that contains the catalytically essential cysteine and arginine residues. The position of the invariant cysteine residue within the phosphate binding site is consistent with its role as a nucleophile in the catalytic reaction. The structure of PTP1B should serve as a model for other members of the PTP family and as a framework for understanding the mechanism of tyrosine dephosphorylation.

Crystal structure of Yersinia protein tyrosine phosphatase at 2.5 A and the complex with tungstate.

Stuckey JA, Schubert HL, Fauman EB, Zhang ZY, Dixon JE, Saper MA
Nature. 1994; 370: 571-5

Protein tyrosine phosphatases (PTPases) and kinases coregulate the critical levels of phosphorylation necessary for intracellular signalling, cell growth and differentiation. Yersinia, the causative bacteria of the bubonic plague and other enteric diseases, secrete an active PTPase, Yop51, that enters and suppresses host immune cells. Though the catalytic domain is only approximately 20% identical to human PTP1B, the Yersinia PTPase contains all of the invariant residues present in eukaryotic PTPases, including the nucleophilic Cys 403 which forms a phosphocysteine intermediate during catalysis. We present here structures of the unliganded (2.5 A resolution) and tungstate-bound (2.6 A) crystal forms which reveal that Cys 403 is positioned at the centre of a distinctive phosphate-binding loop. This loop is at the hub of several hydrogen-bond arrays that not only stabilize a bound oxyanion, but may activate Cys 403 as a reactive thiolate. Binding of tungstate triggers a conformational change that traps the oxyanion and swings Asp 356, an important catalytic residue, by approximately 6 A into the active site. The same anion-binding loop in PTPases is also found in the enzyme rhodanese.

PAC-1: a mitogen-induced nuclear protein tyrosine phosphatase.

Rohan PJ, Davis P, Moskaluk CA, Kearns M, Krutzsch H, Siebenlist U, Kelly K
Science. 1993; 259: 1763-6

Tyrosine phosphorylation of proteins is required for signal transduction in cells and for growth regulation. A mitogen-induced gene (PAC-1) has been cloned from human T cells and encodes a 32-kilodalton protein that contains a sequence that defines the enzymatic site of known protein phosphotyrosine phosphatases (PTPases). Other than this sequence, PAC-1 is different from several other known related PTPases exemplified by PTP-1b. PAC-1 is similar to a phosphatase induced by mitogens or heat shock in fibroblasts, a yeast gene, and a vaccinia virus-encoded serine-tyrosine phosphatase (VH1). PAC-1 was predominantly expressed in hematopoietic tissues and localized to the nucleus in transfected COS-7 cells and in mitogen-stimulated T cells.