The extended human PTPome: a growing tyrosine phosphatase family

Abstract

Tyr phosphatases are, by definition, enzymes that dephosphorylate phospho‐Tyr (pTyr) from proteins. This activity is found in several structurally diverse protein families, including the protein Tyr phosphatase (PTP), arsenate reductase, rhodanese, haloacid dehalogenase (HAD) and His phosphatase (HP) families. Most of these families include members with substrate specificity for non‐pTyr substrates, such as phospho‐Ser/phospho‐Thr, phosphoinositides, phosphorylated carbohydrates, mRNAs, or inorganic moieties. A Cys is essential for catalysis in PTPs, rhodanese and arsenate reductase enzymes, whereas this work is performed by an Asp in HAD phosphatases and by a His in HPs, via a catalytic mechanism shared by all of the different families. The category that contains most Tyr phosphatases is the PTP family, which, although it received its name from this activity, includes Ser, Thr, inositide, carbohydrate and RNA phosphatases, as well as some inactive pseudophosphatase proteins. Here, we propose an extended collection of human Tyr phosphatases, which we call the extended human PTPome. The addition of new members (SACs, paladin, INPP4s, TMEM55s, SSU72, and acid phosphatases) to the currently categorized PTP group of enzymes means that the extended human PTPome contains up to 125 proteins, of which ~ 40 are selective for pTyr. We set criteria to ascribe proteins to the extended PTPome, and summarize the more important features of the new PTPome members in the context of their phosphatase activity and their relationship with human disease.

EYA1's Conformation Specificity in Dephosphorylating Phosphothreonine in Myc and Its Activity on Myc Stabilization in Breast Cancer

“…Among the three short motifs, the first motif, DXDXT/S (red), is also highly conserved in aspartate-based Ser/Thr phosphatase family members (7). Another signature catalytic motif, CX5R (CXXXXXR; aa 532 to 559), conserved in DUSPs, is marked in blue (27). Asterisks indicate the location of the D327N mutation in the ED.…”

“…Since the D327N mutation in the ED alone still retains some threonine phosphatase activity, there is likely another active/regulatory residue(s) in the ED for catalytic binding of EYA1 to the phosphothreonine-Myc substrate. Given the existence of another signature motif, CXXXXXR (aa 418 to 424), conserved in dualspecificity phosphatases (25)(26)(27), it is plausible that the motif may also contribute to EYA1's threonine phosphatase activity. Nonetheless, both the ED and NT appear to interact with substrates to cooperatively increase catalytic binding of EYA1 to regulate EYA1's threonine phosphatase activity, as either domain alone had weaker threonine phosphatase activity.…”

Modulation of VEGF receptor 2 signaling by protein phosphatases

“…However, there is a comparable number of Protein Tyr Kinases (PTKs) and Protein Tyr Phosphatases (PTPs) (∼ 90 vs 107) [1, 4]. Recent classifications have indicated a slightly different number of PTPs [5, 6]. A classification that considers only enzymatically active phosphatases (and includes nonprotein phosphatases) limits PTPs number to 96 [5].…”

“…A classification that considers only enzymatically active phosphatases (and includes nonprotein phosphatases) limits PTPs number to 96 [5]. However, a broader PTP definition, which includes criteria of function, structure and sequence similarities, has increased the total number of PTPs to 125 (namely the extended human PTPome)[6]. …”

Structure of the WipA protein reveals a novel tyrosine protein phosphatase effector from Legionella pneumophila

“…The crystal structure reveals a two-domain structure comprising a metallophosphoesterase attached to an 85-Å-long α-helical hairpin forming a coiled-coil at its tip. Although WipA exhibits a serine/threonine phosphatase fold, it functions preferentially as a protein-tyrosine phosphatase (PTP), even though there are no structural similarities to the general PTP fold (15). Site-directed mutagenesis of key residues in the active site confirm the catalytic mechanism based on a binuclear catalytic center.…”