Protein tyrosine phosphatase

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Protein-tyrosine-phosphatase
1xm2.jpg
Protein tyrosine phosphatase 1, trimer, Human
Identifiers
EC no. 3.1.3.48
CAS no. 79747-53-8
Databases
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BRENDA BRENDA entry
ExPASy NiceZyme view
KEGG KEGG entry
MetaCyc metabolic pathway
PRIAM profile
PDB structures RCSB PDB PDBe PDBsum

Protein tyrosine phosphatases (EC 3.1.3.48, systematic name protein-tyrosine-phosphate phosphohydrolase) are a group of enzymes that remove phosphate groups from phosphorylated tyrosine residues on proteins:

Contents

[a protein]-tyrosine phosphate + H2O = [a protein]-tyrosine + phosphate

Protein tyrosine (pTyr) phosphorylation is a common post-translational modification that can create novel recognition motifs for protein interactions and cellular localization, affect protein stability, and regulate enzyme activity. As a consequence, maintaining an appropriate level of protein tyrosine phosphorylation is essential for many cellular functions. Tyrosine-specific protein phosphatases (PTPase; EC 3.1.3.48) catalyse the removal of a phosphate group attached to a tyrosine residue, using a cysteinyl-phosphate enzyme intermediate. These enzymes are key regulatory components in signal transduction pathways (such as the MAP kinase pathway) and cell cycle control, and are important in the control of cell growth, proliferation, differentiation, transformation, and synaptic plasticity. [1] [2] [3] [4]

Functions

Together with tyrosine kinases, PTPs regulate the phosphorylation state of many important signalling molecules, such as the MAP kinase family. PTPs are increasingly viewed as integral components of signal transduction cascades, despite less study and understanding compared to tyrosine kinases.

PTPs have been implicated in regulation of many cellular processes, including, but not limited to:

Classification

By mechanism

PTP activity can be found in four protein families. [6] [7]

Links to all 107 members of the protein tyrosine phosphatase family can be found in the template at the bottom of this article.

Class I

The class I PTPs, are the largest group of PTPs with 99 members, which can be further subdivided into

Dual-specificity phosphatases (dTyr and dSer/dThr) dual-specificity protein-tyrosine phosphatases. Ser/Thr and Tyr dual-specificity phosphatases are a group of enzymes with both Ser/Thr (EC 3.1.3.16) and tyrosine-specific protein phosphatase (EC 3.1.3.48) activity able to remove the serine/threonine or the tyrosine-bound phosphate group from a wide range of phosphoproteins, including a number of enzymes that have been phosphorylated under the action of a kinase. Dual-specificity protein phosphatases (DSPs) regulate mitogenic signal transduction and control the cell cycle.

LEOPARD syndrome, Noonan syndrome, and metachondromatosis are associated with PTPN11 .

Elevated levels of activated PTPN5 negatively affects synaptic stability and plays a role in Alzheimer's disease, [3] Fragile X syndrome, [4] schizophrenia, [8] and Parkinson's disease. [9] Decreased levels of PTPN5 has been implicated in Huntington's disease, [10] [11] brain ischemia, [12] alcohol use disorder, [13] [14] and stress disorders. [15] [16] Together these findings indicate that only at optimal levels of PTPN5 is synaptic function unimpaired.

Class II

LMW (low-molecular-weight) phosphatases, or acid phosphatases, act on tyrosine phosphorylated proteins, low-MW aryl phosphates and natural and synthetic acyl phosphates. [17] [18]

The class II PTPs contain only one member, low-molecular-weight phosphotyrosine phosphatase (LMPTP).

Class III

Cdc25 phosphatases (dTyr and/or dThr)

The Class III PTPs contains three members, CDC25 A, B, and C

Class IV

These are members of the HAD fold and superfamily, and include phosphatases specific to pTyr and pSer/Thr as well as small molecule phosphatases and other enzymes. [19] The subfamily EYA (eyes absent) is believed to be pTyr-specific, and has four members in human, EYA1, EYA2, EYA3, and EYA4. This class has a distinct catalytic mechanism from the other three classes. [20]

By location

Based on their cellular localization, PTPases are also classified as:

Common elements

All PTPases, other than those of the EYA family, carry the highly conserved active site motif C(X)5R (PTP signature motif), employ a common catalytic mechanism, and possess a similar core structure made of a central parallel beta-sheet with flanking alpha-helices containing a beta-loop-alpha-loop that encompasses the PTP signature motif. [23] Functional diversity between PTPases is endowed by regulatory domains and subunits.

Low-molecular-weight phosphotyrosine protein phosphatase
PDB 1phr EBI.jpg
Structure of a low-molecular-weight phosphotyrosine protein phosphatase. [24]
Identifiers
SymbolLMWPc
Pfam PF01451
InterPro IPR017867
SMART SM00226
SCOP2 1phr / SCOPe / SUPFAM
CDD cd00115
Protein-tyrosine phosphatase
PDB 1ypt EBI.jpg
Structure of Yersinia protein tyrosine phosphatase. [25]
Identifiers
SymbolY_phosphatase
Pfam PF00102
Pfam clan CL0031
InterPro IPR000242
SMART SM00194
PROSITE PS50055
SCOP2 1ypt / SCOPe / SUPFAM
CDD cd00047
Dual-specificity phosphatase, catalytic domain
PDB 1vhr EBI.jpg
Structure of the dual-specificity protein phosphatase VHR. [26]
Identifiers
SymbolDSPc
Pfam PF00782
Pfam clan CL0031
InterPro IPR000340
PROSITE PDOC00323
SCOP2 1vhr / SCOPe / SUPFAM
CDD cd14498
Protein-tyrosine phosphatase, SIW14-like
PDB 1xri EBI.jpg
Structure of a putative phosphoprotein phosphatase from Arabidopsis thaliana. [27]
Identifiers
SymbolY_phosphatase2
Pfam PF03162
Pfam clan CL0031
InterPro IPR004861
CDD cd14528
Protein-tyrosine phosphatase-like, PTPLA
Identifiers
SymbolPTPLA
Pfam PF04387
InterPro IPR007482

Expression pattern

Individual PTPs may be expressed by all cell types, or their expression may be strictly tissue-specific. Most cells express 30% to 60% of all the PTPs, however hematopoietic and neuronal cells express a higher number of PTPs in comparison to other cell types. T cells and B cells of hematopoietic origin express around 60 to 70 different PTPs. The expression of several PTPS is restricted to hematopoietic cells, for example, LYP, SHP1, CD45, and HePTP. [28] The expression of PTPN5 is restricted to the brain. Differential expression of PTPN5 is found in many brain regions, with no expression in the cerebellum. [29] [30] [31]

Related Research Articles

A protein phosphatase is a phosphatase enzyme that removes a phosphate group from the phosphorylated amino acid residue of its substrate protein. Protein phosphorylation is one of the most common forms of reversible protein posttranslational modification (PTM), with up to 30% of all proteins being phosphorylated at any given time. Protein kinases (PKs) are the effectors of phosphorylation and catalyse the transfer of a γ-phosphate from ATP to specific amino acids on proteins. Several hundred PKs exist in mammals and are classified into distinct super-families. Proteins are phosphorylated predominantly on Ser, Thr and Tyr residues, which account for 79.3, 16.9 and 3.8% respectively of the phosphoproteome, at least in mammals. In contrast, protein phosphatases (PPs) are the primary effectors of dephosphorylation and can be grouped into three main classes based on sequence, structure and catalytic function. The largest class of PPs is the phosphoprotein phosphatase (PPP) family comprising PP1, PP2A, PP2B, PP4, PP5, PP6 and PP7, and the protein phosphatase Mg2+- or Mn2+-dependent (PPM) family, composed primarily of PP2C. The protein Tyr phosphatase (PTP) super-family forms the second group, and the aspartate-based protein phosphatases the third. The protein pseudophosphatases form part of the larger phosphatase family, and in most cases are thought to be catalytically inert, instead functioning as phosphate-binding proteins, integrators of signalling or subcellular traps. Examples of membrane-spanning protein phosphatases containing both active (phosphatase) and inactive (pseudophosphatase) domains linked in tandem are known, conceptually similar to the kinase and pseudokinase domain polypeptide structure of the JAK pseudokinases. A complete comparative analysis of human phosphatases and pseudophosphatases has been completed by Manning and colleagues, forming a companion piece to the ground-breaking analysis of the human kinome, which encodes the complete set of ~536 human protein kinases.

PTPN11

Tyrosine-protein phosphatase non-receptor type 11 (PTPN11) also known as protein-tyrosine phosphatase 1D (PTP-1D), Src homology region 2 domain-containing phosphatase-2 (SHP-2), or protein-tyrosine phosphatase 2C (PTP-2C) is an enzyme that in humans is encoded by the PTPN11 gene. PTPN11 is a protein tyrosine phosphatase (PTP) Shp2.

PTPN6 Protein-coding gene in the species Homo sapiens

Tyrosine-protein phosphatase non-receptor type 6, also known as Src homology region 2 domain-containing phosphatase-1 (SHP-1), is an enzyme that in humans is encoded by the PTPN6 gene.

PTPN1

Tyrosine-protein phosphatase non-receptor type 1 also known as protein-tyrosine phosphatase 1B (PTP1B) is an enzyme that is the founding member of the protein tyrosine phosphatase (PTP) family. In humans it is encoded by the PTPN1 gene. PTP1B is a negative regulator of the insulin signaling pathway and is considered a promising potential therapeutic target, in particular for treatment of type 2 diabetes. It has also been implicated in the development of breast cancer and has been explored as a potential therapeutic target in that avenue as well.

PTPN12

Tyrosine-protein phosphatase non-receptor type 12 is an enzyme that in humans is encoded by the PTPN12 gene.

PTPRA

Receptor-type tyrosine-protein phosphatase alpha is an enzyme that in humans is encoded by the PTPRA gene.

PTPN13

Tyrosine-protein phosphatase non-receptor type 13 is an enzyme that in humans is encoded by the PTPN13 gene.

PTPRF

Receptor-type tyrosine-protein phosphatase F is an enzyme that in humans is encoded by the PTPRF gene.

PTPN2

Tyrosine-protein phosphatase non-receptor type 2 is an enzyme that in humans is encoded by the PTPN2 gene.

PTPN7 Protein-coding gene in the species Homo sapiens

Protein tyrosine phosphatase non-receptor type 7 is an enzyme that in humans is encoded by the PTPN7 gene.

PTPRR

Protein tyrosine phosphatase receptor-type R is an enzyme that in humans is encoded by the PTPRR gene.

PTPN18

Tyrosine-protein phosphatase non-receptor type 18 is an enzyme that in humans is encoded by the PTPN18 gene.

PTPN9

Tyrosine-protein phosphatase non-receptor type 9 is an enzyme that in humans is encoded by the PTPN9 gene.

PTPN14 Protein-coding gene in the species Homo sapiens

Tyrosine-protein phosphatase non-receptor type 14 is an enzyme that in humans is encoded by the PTPN14 gene.

PTPN4

Tyrosine-protein phosphatase non-receptor type 4 is an enzyme that in humans is encoded by the PTPN4 gene.

PTPN5

Protein tyrosine phosphatase non-receptor type 5 is an enzyme that in humans is encoded by the PTPN5 gene.

PTPN21

Tyrosine-protein phosphatase non-receptor type 21 is an enzyme that in humans is encoded by the PTPN21 gene.

A non-receptor tyrosine kinase (nRTK) is a cytosolic enzyme that is responsible for catalysing the transfer of a phosphate group from a nucleoside triphosphate donor, such as ATP, to tyrosine residues in proteins. Non-receptor tyrosine kinases are a subgroup of protein family tyrosine kinases, enzymes that can transfer the phosphate group from ATP to a tyrosine residue of a protein (phosphorylation). These enzymes regulate many cellular functions by switching on or switching off other enzymes in a cell.

YopH, N-terminal

In molecular biology, YopH, N-terminal refers to an evolutionary conserved protein domain. This entry represents the N-terminal domain of YopH protein tyrosine phosphatase (PTP).

Tyrosine phosphorylation Phosphorylation of peptidyl-tyrosine

Tyrosine phosphorylation is the addition of a phosphate (PO43−) group to the amino acid tyrosine on a protein. It is one of the main types of protein phosphorylation. This transfer is made possible through enzymes called tyrosine kinases. Tyrosine phosphorylation is a key step in signal transduction and the regulation of enzymatic activity.

References

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