Dual-specificity phosphatase (DUSP; DSP) is a form of

phosphatase In biochemistry, a phosphatase is an enzyme that uses water to cleave a phosphoric acid Ester, monoester into a phosphate ion and an Alcohol (chemistry), alcohol. Because a phosphatase enzyme catalysis, catalyzes the hydrolysis of its Substrate ...

that can act upon

tyrosine -Tyrosine or tyrosine (symbol Tyr or Y) or 4-hydroxyphenylalanine is one of the 20 standard amino acids that are used by cells to synthesize proteins. It is a conditionally essential amino acid with a polar side group. The word "tyrosine" is ...

serine Serine (symbol Ser or S) is an α-amino acid that is used in the biosynthesis of proteins. It contains an α- amino group (which is in the protonated − form under biological conditions), a carboxyl group (which is in the deprotonated − ...

threonine Threonine (symbol Thr or T) is an amino acid that is used in the biosynthesis of proteins. It contains an α-amino group (which is in the protonated −NH form when dissolved in water), a carboxyl group (which is in the deprotonated −COO− ...

residues. There are several families of dual-specificity phosphatase enzymes in mammals. All share a similar catalytic mechanism, by which a conserved

cysteine Cysteine (; symbol Cys or C) is a semiessential proteinogenic amino acid with the chemical formula, formula . The thiol side chain in cysteine enables the formation of Disulfide, disulfide bonds, and often participates in enzymatic reactions as ...

residue forms a covalent intermediate with the phosphate group to be eliminated. The residues surrounding their catalytic core obey a rather strict consensus: His-Cys-x-x-x-x-x-Arg-Ser. The serine side chain and an additional conserved

aspartate Aspartic acid (symbol Asp or D; the ionic form is known as aspartate), is an α-amino acid that is used in the biosynthesis of proteins. The L-isomer of aspartic acid is one of the 22 proteinogenic amino acids, i.e., the building blocks of protein ...

play a central role in the elimination of the Cys-linked intermediate, thus completing their enzymatic cycle. The main difference between tyrosine-specific phosphatases and dual-specificity phosphatases lies in the width of the latter enzymes' catalytic pocket: thus they can accommodate

phosphorylated serine Phosphoserine (abbreviated as SEP or J) is an ester of serine and phosphoric acid. Phosphoserine is a component of many proteins as the result of posttranslational modifications. The phosphorylation of the alcohol functional group in serine to pro ...

or threonine side chains as well as phosphorylated tyrosines.

Classification

The human genome encodes at least 61 different DUSP proteins. The following major groups or families of DUSPs were identified: * Slingshot phosphatases: There are three members of this family ( SSH1L,

SSH2 Protein phosphatase Slingshot homolog 2 is an enzyme that in humans is encoded by the ''SSH2'' gene In biology, the word gene has two meanings. The Mendelian gene is a basic unit of heredity. The molecular gene is a sequence of nucleotide ...

L and SSH3L) with broad specificity. They contain SH3-binding motifs as well as F-actin binding motifs, thus they are generally believed to play a role in the regulation of cytoskeletal rearrangements. In accordance with their proposed rule, proteins like ADF, cofilin and LIMK1 are slingshot substrates. * Phosphatases of Regenerating Liver (PRLs): Three PRL genes were described in mammals (PRL-1, PRL-2 and PRL-3). They share a high sequence identity and possess an N-terminal prenylation sequence (CAAX box). Despite their up-regulation in colorectal cancer, the role and substrate specificity of PRLs is poorly known. *

Cdc14 ''Cdc14'' and Cdc14 are a gene and its protein product respectively. Cdc14 is found in most of the eukaryotes. Cdc14 was defined by Hartwell in his famous screen for loci that control the cell cycle of Saccharomyces cerevisiae. Cdc14 was later sho ...

phosphatases: The four mammalian Cdc14 proteins (named KAP, Cdc14A, Cdc14B and PTP9Q22) play a crucial role in cell cycle regulation by dephosphorylating cyclin-dependent kinases, most importantly CDK2. * PTEN and

myotubularin Myotubularin domain represents a region within eukaryotic myotubularin-related proteins that is sometimes found with the GRAM domain. Myotubularin is a dual-specific lipid phosphatase that dephosphorylates phosphatidylinositol 3-phosphate and ...

phosphatases There are five PTEN-like phosphatases encoded in the human genome. Though structurally related to other DUSPs, these are not strictly phosphorotein-phosphatases, since their most important substrates are phosphorylated inositol lipids. Myotubularins similarly display a preference towards certain phosphatidyl inositols. * Mitogen-activated protein Kinase Phosphatases (MKPs) MKPs form a rather large family, with some 11 well-characterized members. They are responsible for the dephosphorylation of active mitogen-activated protein kinases (MAPKs). In accordance with this role, several (but not all) MKPs contain an additional, N-terminal domain. Although structurally similar to Cdc14, this extra domain is inactive, and plays a role in substrate recruitment. The surface of this substrate-binding domain mimics the D-motifs found in intrinsically disordered substrates of MAPKs. * In addition, there are several dual-specificity phosphatases lacking close relatives. Most of these atypical DUSPs are poorly characterized. Some of them are probably inactive, and only mediate protein-protein interactions.

References

{{Protein tyrosine phosphatases Enzymes