Dual-specificity protein phosphatases

Figure 8 Kinase-catalyzed phosphorylation and phosphatases-catalyzed dephosphorylation reactions, (a) Catalytic mechanism of protein kinases (b) Catalytic mechanism of bimetallic pSer/pThr or dual specifity protein phosphatases (c) Catalytic mechanism of pTyr phosphatases.

ERK dual-specificity protein phosphatase removes phosphorylation of ERKl and ERK2 at T202 and Y204 residues... 

Sodeoka M, Sampe R, Kojima S, Baba Y, Usui T, Ueda K, Osada H. Synthesis of a tetronic acid library focused on inhibitors of tyrosine and dual-specificity protein phosphatases and its evaluation regarding VHR and Cdc25B inhibition. J. Med. Chem. 2001 44 3216-3222. 

Stevastelins A, A3, B, B3, C3, D3 and E3 (Fig. 45) were discovered by Morino et al. in 1996, as immunosuppressants that inhibit dual-specificity protein phosphatases from Penicillium sp.. ... 

Martell KJ, Angelotti T, Ullrich A. The VHl-like dual-specificity protein tyrosine phosphatases. Mol Cells 1998 8 2-11. 

On the other hand, a particular protein function can be realized with different protein folds, and an example of this are protein phosphatases. Protein phosphatases feature two distinctively different catalytic mechanisms for hydrolytically cleaving phosphorylated amino acid residues. The active sites of serine/threonine protein phosphatases (PPs) contain two metal centers that directly activate a water molecule for nucleophilic attack of the phosphate ester bond. In contrast, protein tyrosine phosphatases (PTPs) [105] possess a Cys residue present in the active site loop containing the conserved PTP signature motif HCXXXXXRS. The Cys sidechain acts as the attacking nucleophile in the formation of a phosphocysteine intermediate, which is eventually hydrolyzed by a water molecule [106], The same catalytic mechanism is also shared by dual-specificity phosphatases (see below). 

Fig. 3.8 The protein tyrosine phosphatases (PTPs) with the C(X)gR motif are divided into tyrosine-specific PTPs the VHl-like dual specificity, serine/threonine- and tyrosine-specific phosphatases the CDC25 phosphatase and the low molecular weight (LMW) phosphatases. The low molecular weight phosphatases are acid phosphatases without distinct regulatory or targeting domains. Their function is not known. The tyosiiie-speoifio phosphatases are further subdivided into receptor-like and non-reoeptor-like phosphatases. (This scheme is reproduced with permission of the authors and Trends Biochem. Sci. from ref. 76.)...

Pulido B., Hooft van Huijsduijnen R (2008) Protein tyrosine phosphatases dual-specificity phosphatases in health and disease. FEBS J 275 848-866... 

Arrest in Gx phase can now be achieved in at least two ways, depending on the substrates of the Chkl and Chk2 enzymes. In one rapid way, the dual specificity phosphatase Cdc25C is phosphorylated on Ser 123 and is thereby targeted for ubiquitina-tion and degradation in the proteasome pathway. The lack of this enzyme locks the CDK2 kinase in the inactive form phosphorylated on threonine 14 and tyrosine 15.The cyclin E-CDK2 complex that is required for entry into S phase is inhibited, and the cell cycle arrests at Gj/S. It should be noted that the scheme in Fig. 13.19 is only a minimal scheme that does not address the participation of numerous other proteins that function as adaptors or structural proteins in these processes. 

The PTPs catalyze the hydrolysis of phosphorylated tyrosine residues in proteins, to yield the free tyrosine side chains and inorganic phosphate. They are classified according to substrate specificity (1) tyrosine-specific PTPs, such as the Yersinia PTP (YopH) and the mammalian PTPIB and PTPl, which in vivo hydrolyze only pTyr residues as well as (2) the dual-specificity phosphatases (DSPs), such as the human VHR and Cdc25, which hydrolyze pTyr and pSer and pThr residues of protein substrates. Based on their cellular localization, PTPs are classified as receptor-like or intracellular. ... 

PTPs are classified on the basis of their structure and sequence [3], They can be subgrouped into classical nonreceptor-type nontransmembrane PTPs, receptorlike membrane-localized PTPs, and the dual-specificity phosphatases (DUSPs) [4], Classical PTPs mostly recognize phospho-tyrosine as their substrate, whereas DUSPs are also known to dephosphorylate proteins on serine or threonine, and even phospholipids or RNA can be substrates [3], All PTPs contain a conserved CXXXXXR motive (single-letter amino acid code). The cysteine is the catalytically active moiety. Another residue that is involved in the catalytic mechanism (with some exceptions [5]) is an aspartic acid in the so-called WPD (Trp-Pro-Asp) loop, which is distinct from the active site [4] (Figure 1). 

Some phosphatases are nonspecific, catalyzing the hydrolysis of a wide variety of substrates. Other phosphatases are small-molecule specific and hydrolyze a particular small-molecule phosphate ester or structurally similar substrates. Phosphoprotein-specific phosphatases accept particular phosphorylated proteins or peptides as substrates. The phosphoprotein-specific phosphatases can be subdivided into subgroups those specific for proteins phosphorylated on tyrosine those specific for proteins phosphorylated on serine or threonine and the so-called dual-specific enzymes, which accept both classes of phosphorylated proteins. More recently, a group of protein histidine phosphatases has been described. 

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