2P6X , 2QCJ , 2QCT , 3BRH , 3H2X , 3OLR , 3OMH , 4J51
56-439: 26191 19260 ENSG00000134242 ENSMUSG00000027843 Q9Y2R2 P29352 NM_001193431 NM_001308297 NM_012411 NM_015967 NM_008979 NP_001180360 NP_001295226 NP_036543 NP_057051 NP_033005 Protein tyrosine phosphatase non-receptor type 22 (PTPN22) is a cytoplasmatic protein encoded by gene PTPN22 and a member of PEST family of protein tyrosine phosphatases. This protein
112-524: A splenomegaly and a lymphadenopathy . In these older mice we can see an increased number of the T cells with phenotype of the effector/memory T cells ( CD44 , CD62L ), which have higher expression of the PTPN22 than naive T cells in Wild Type mice. The expansion of those T cells is supported by the PTPN22 deficiency. A compartment of Treg cell is also influenced by the PTPN22 deficiency in vivo . Same as with
168-461: A T cell compartment and an antibody production, PTPN22-deficient mice do not show signs of any autoimmune disease. In 2004, Bottini et al. discovered the single-nucleotide polymorphism in the PTPN22 gene at nucleotide 1858. In this variant of the gene, normally occurring cytosine is substituted by thymine (C1858T). This cytosine encodes the codon for an amino acid arginine in the position 620 of
224-400: A TCR signaling. The mutant PTPN22, which is unable to bind CSK, is effectively recruited to a plasma membrane. Another interaction partner of the PTPN22 is TRAF3 . This protein bind the PTPN22 and regulate its translocalization to a plasma membrane, in the absence of TRAF3 there is a bigger amount of the PTPN22 localized at a plasma membrane. It was revealed that PTPN22 is regulated by
280-403: A bigger ability to obtain an effector phenotype. Next to a TCR signaling PTPN22 regulates an adhesiveness and a motility of T cells. PTPN22-deficient T cells have a prolonged interval of contact with an antigen presenting cell , which present a low affinity peptide. With a high affinity peptide the difference is not detectable. Part of the reason of the increased adhesiveness of those T cells
336-428: A critical family for anti-viral immune response, could be influenced by natural selection during Human species evolution. The positive selection has been found on the amino acid site Val129 (NP_006075.3:p.Ser129Val) of human IRF9. The ancestral state (Ser129) is conserved among mammals, while the novel state (Val129) was fixed before the "out-of-Africa" event ~ 500,000 years ago. This young amino acid (Val129) may serve as
392-432: A desphosphorylating phosphatase, re-ligation can be avoided. Alkaline phosphatases , which remove the phosphate group present at the 5′ terminus of a DNA molecule, are often sourced naturally, most commonly from calf intestine, and are abbreviated as CIP . The natural selection power for dephosphorylation is less understood. A recent study has found that IRF9, which is from the interferon-regulatory factors family (IRFs),
448-539: A driver of plasticity in responding to varied temperature. Accelerated protein dephosphorylation in photosynthetic thylakoid membranes occurs at elevated temperatures, directly impacting the desphosphorylation of key proteins within the photosystem II complex. Excessive dephosphorylation of the membrane ATPases and proton pumps in the gastrointestinal tract leads to higher secretory rates of caustic peptic acids. These result in heartburn and esophagitis. In combination with Helicobacter pylori infection, peptic ulcer disease
504-444: A free energy "currency" in all living organisms. In a spontaneous dephosphorylation reaction 30.5 kJ/mol is released, which is harnessed to drive cellular reactions. Overall, nonspontaneous reactions coupled to the dephosphorylation of ATP are spontaneous, due to the negative free energy change of the coupled reaction. This is important in driving oxidative phosphorylation. ATP is dephosphorylated to ADP and inorganic phosphate. On
560-550: A phosphorylation. PTPN22 is phosphorylated on the serine in the position 751 by the protein PKC (most probably isoform PKCα) after activation of a T cell. This phosphorylation negatively regulates the TCR-suppressing function of the PTPN22. It also suppresses the polyubiquitination of PTPN22, which targets this protein for degradation , and by this mean, it prolongs half-life of the PTPN22. Phosphorylared PTPN22 interacts better with
616-527: A proximal TCR signaling only after their activation. PTPN22 can dephosphorylate those proteins and decrease the activating signal obtained by a T cell. Dephosphorylation of kinases LCK and ZAP70 by a PTPN22 is specific concerning the phosphorylated tyrosine in those proteins – only the Y394 of LCK and the Y493 of ZAP70 are dephosphorylated. In the absence of PTPN22, an activated T cell receive a stronger activation signal, which
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#1733086210754672-875: A role in Alzheimer's disease , Fragile X syndrome , schizophrenia , and Parkinson's disease . Decreased levels of PTPN5 has been implicated in Huntington's disease , brain ischemia , alcohol use disorder , and stress disorders. Together these findings indicate that only at optimal levels of PTPN5 is synaptic function unimpaired. LMW (low-molecular-weight) phosphatases, or acid phosphatases , act on tyrosine phosphorylated proteins, low-MW aryl phosphates and natural and synthetic acyl phosphates. The class II PTPs contain only one member, low-molecular-weight phosphotyrosine phosphatase ( LMPTP ). Cdc25 phosphatases (dTyr and/or dThr) The Class III PTPs contains three members, CDC25 A , B , and C These are members of
728-561: A signal from a TCR, phosphorylating other proteins and creating a multi-protein complex, which activates downstream signaling pathways. PTPN22 possess the ability to dephosphorylate proteins included in proximal events of the TCR signaling and serves as an important negative regulator of a T cell activation. PTPN22 is able to bind the LCK with phosphorylated Y394, the phosphorylated ZAP70 and the phosphorylated ζ chain of CD3 complex. Thus, it binds molecules of
784-639: A signaling pathway activating a T cell. The first event of this pathway is activation of the SRC family kinase LCK by a dephosphorylation of its C terminal inhibition tyrosine (Y505) and by a phosphorylation of its activation tyrosine (Y394). LCK then phosphorylate tyrosines in the CD3 complex creating a docking site for the SH2 domain of the SYK family kinase ZAP70 , which is there phosphorylated too. The Phosphorylated ZAP70 then propagate
840-399: 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
896-478: Is a fundamental part of the regulation of every physiologic process. Phosphorylation involves the covalent modification of the hydroxyl with a phosphate group through the nucleophilic attack of the alpha phosphate in ATP by the oxygen in the hydroxyl. Dephosphorylation involves removal of the phosphate group through a hydration reaction by addition of a molecule of water and release of the original phosphate group, regenerating
952-592: Is a gain-of-function mutation. Overview of all the structural information available in the PDB for UniProt : Q9Y2R2 (Tyrosine-protein phosphatase non-receptor type 22) at the PDBe-KB . Protein tyrosine phosphatase 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: Protein tyrosine (pTyr) phosphorylation
1008-457: Is a key process involved in cell signalling , protein phosphatases are implicated in conditions such as cardiac disease, diabetes, and Alzheimer's disease. The discovery of dephosphorylation came from a series of experiments examining the enzyme phosphorylase isolated from rabbit skeletal muscle. In 1955, Edwin Krebs and Edmond Fischer used radiolabeled ATP to determine that phosphate is added to
1064-405: Is a spontaneous formation of large germinal centers in spleens and peyer's patches . This formation of germinal centers is dependent on the costimulation molecule CD40L and it is another consequence of the T cell dysregulation. PTPN22-deficient mice have increased levels of antibodies. However, there is no increase in levels of autoantibodies . Despite those effects of the PTPN22 deficiency on
1120-432: Is also a change of the effector Treg cells : central Treg cells ratio in favor of the effector Treg cells. PTPN22 deficiency increases abilities of Treg cells to survive, differentiation of Treg cells from naive T cells, but not the ability to proliferate in vivo , and it also supports transition of central Treg cells to effector Treg cells. One of the reasons, of the increased survival of PTPN22-deficient Treg cells,
1176-543: Is also called "PEST-domain Enriched Phosphatase" ("PEP") or "Lymphoid phosphatase" ("LYP"). The name LYP is used strictly for the human protein encoded by PTPN22 , but the name PEP is used only for its mouse homolog . However, both proteins have similar biological functions and show 70% identity in amino acid sequence. PTPN22 functions as a negative regulator of T cell receptor (TCR) signaling , which maintains homeostasis of T cell compartment. Gene PTPN22
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#17330862107541232-655: Is caused by the elevated pH dephosphorylation elicits. The microtubule-associated protein tau is abnormally hyperphosphorylated when isolated from the brain of patients who suffer from Alzheimer's disease . This is due to the dysfunction of dephosphorylation mechanisms at specific amino acids on the tau protein. Tau dephosphorylation is catalysed by protein phosphatase-2A and phosphatase-2B. Deficiency or modification of one or both proteins may be involved in abnormal phosphorylation of tau in Alzheimer's disease Dephosphorylation has also been linked to cardiac disease , particularly
1288-600: Is located on the p arm of the human chromosome 1. It is nearly 58 000 base pairs long and contains 21 exons . In the case of mouse genome, it is located on the q arm of the chromosome 3. It is nearly 55 700 base pairs long and contains 23 exons. PTPN22 is composed from 807 amino acids, and it weighs 91,705 kDa . On its N terminus it possesses catalytic domain , which shows the highest level of conservation between human and mouse proteins. Other parts of PTPN22 are less conserved. After catalytic domain PTPN22 has approximately 300 amino acids long domain called "Interdomain". On
1344-406: Is referred to as phosphoregulation. The deregulation of phosphorylation can lead to disease. During the synthesis of proteins, polypeptide chains, which are created by ribosomes translating mRNA, must be processed before assuming a mature conformation. The dephosphorylation of proteins is a mechanism for modifying behavior of a protein, often by activating or inactivating an enzyme . Components of
1400-399: Is reflected by a greater influx of Ca cations into the cytosol , bigger phosphorylation of an LCK, ZAP70 and ERK and larger expansion of those cells . The inhibitory effect on a TCR signaling was also verified with the usage of PTPN22 inhibitor on a Jurkat T cell line and on human primary T cells, and also with the experiments of PTPN22 overexpression in vitro . The expression of PTPN22
1456-510: Is that enhanced TCR signaling results in a higher activation of the RAP1 and a boosted inside-out signaling to activate the adhesive molecule LFA-1 . In migrating T cells we can see the polarized localization of the PTPN22 at the leading edge of a migrating T cell, where it colocalizes with its substrates LCK and ZAP70. A downregulation of the PTPN22 increases motility, adhesivity and levels of phosphorylated LCK and phosphorylated ZAP70 in those cells. On
1512-416: Is that those cells have upregulated expression of GITR , which increases their expansion in vivo . Treatment of PTPN22-deficient mice with an anti-GITR-L blocking antibody suppresses the expansion of Treg cells. PTPN22 deficiency does not impair the suppressive function of Treg cells. Actually there are some articles suggesting that PTPN22-deficient Treg cells possess an enhanced suppressive function or have
1568-600: Is the conversion of ATP to ADP and inorganic phosphate. Dephosphorylation employs a type of hydrolytic enzyme, or hydrolase , which cleaves ester bonds. The prominent hydrolase subclass used in dephosphorylation is phosphatase , which removes phosphate groups by hydrolysing phosphoric acid monoesters into a phosphate ion and a molecule with a free hydroxyl (–OH) group. The reversible phosphorylation-dephosphorylation reaction occurs in every physiological process, making proper function of protein phosphatases necessary for organism viability. Because protein dephosphorylation
1624-619: Is upregulated after an activation of T cells and an antigen-experienced T cell have higher expression of PTPN22 than a naive T cell . The regulatory function of PTPN22 is particularly important during an activation by low affinity peptides. In the absence of PTPN22, T cell cannot discriminate between strong and weak antigens sufficiently and those T cells become more responsive, which can be detected like increased upregulation of transcription factors and CD69 , increased ERK phosphorylation , increased ability to expand in vivo and to produce cytokines . Increased responsiveness can also break
1680-406: The C terminus of PTPN22 there are 4 proline -rich motifs (P1 - P4), which can mediate interactions with other proteins. P1 motif is the most important among them, because it is crucial for binding of CSK kinase, and allele encoding PTPN22 with mutated P1 motif is associated with increased risk of numerous autoimmune diseases . A T cell receptor activation by a cognate peptide triggers
1736-504: The HAD fold and superfamily, and include phosphatases specific to pTyr and pSer/Thr as well as small molecule phosphatases and other enzymes. 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. Based on their cellular localization, PTPases are also classified as: All PTPases, other than those of
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1792-567: The linear protein structure , but the mutation to thymine cause change of an arginine to a tryptophan (R620W). The amino acid 620 is placed in the P1 motif, which is involved in the association with CSK and the mutation to tryptophan diminish the ability of the PTPN22 to bind CSK. The article reporting the existence of this variant also discovered that it is more frequent in Diabetes mellitus type 1 patients. The association of C1858T allele with type 1 diabetes
1848-490: 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: PTP activity can be found in four protein families. Links to all 107 members of
1904-493: 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
1960-438: The tolerance against low affinity self-antigens and is well visible, when PTPN22-deficient T cells get into a lymphopenic environment. One particular population of T cells, which is influenced by a PTPN22 deficiency is the population of regulatory T cells (Treg cells). PTPN22-deficient mice contain higher amount of Treg cells in lymph nodes and spleens and this difference is more visible with increasing age of mice. There
2016-454: The CSK which hold PTPN22 away from a plasma membrane, where it can dephosphorylate proteins of a TCR signaling pathway. PTPN22 with the mutated serine 751 has shorter half-life, enhanced recruitment to plasma membrane and reduced interaction with CSK. Young PTPN22-deficient mice do not display any abnormality in peripheral lymphoid organs , but older PTPN22-deficient mice (older than 6 months) develop
2072-637: 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. Functional diversity between PTPases is endowed by regulatory domains and subunits. 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
2128-425: The P1 motif greatly diminish the inhibitory effect of the PTPN22 on a TCR signaling. The Interaction of those enzymes is needed for their optimal function and the inhibition of TCR signaling. It was also proposed that the interaction of PTPN22 and CSK regulate a localization of the PTPN22 and a dissociation of this complex enables translocation of the PTPN22 to lipid rafts of a plasma membrane , where it can inhibit
2184-434: The PTPN22 bare proline-rich motifs providing binding sites for putative interaction partners. One of those interaction partners is the cytoplasmatic tyrosine kinase CSK, which is a negative regulator of SRC family kinases and a TCR signaling as well as the PTPN22. CSK binds two prolin-rich motifs (P1 and P2) in the structure of PTPN22 through its SH3 domain and the P1 motif is more important in this interaction. A deletion of
2240-488: 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 . The expression of PTPN5 is restricted to the brain, and differs between brain regions , with no expression in
2296-408: The acidity of the gastrointestinal tract, reducing the symptoms of acid-related diseases. The resulting change in pH decreases survival of the bacteria H.pylori , a major cause of peptic ulcer disease. Once the proton pump inhibitor eradicates this bacteria within the gut, reversing erosive reflux. Treating heart disease has improved with the use of drugs that inhibit AMPK via dephosphorylation. In
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2352-823: The alteration of actin-myosin interactions that are key for providing the underlying force of a heartbeat. Dephosphorylation is a key part of the myosin cycling kinetics that directly control the actin-myosin interactions. When the dephosphorylation process is interrupted, calcium dependent cardiac contraction is impaired or fully disabled. Research has also suggested that modifications to dephosphorylation impact physiological processes implicated in Diabetes mellitus . The kinetics of dephosphorylation of insulin receptor substrate-1/2, Akt, and ERK1/2, phosphoproteins are shown to be involved in insulin receptor signaling, and in vitro models demonstrate that changes to dephosphorylation kinetics impact upstream and downstream insulin stimulation. Inhibition of proton pumps significantly decreases
2408-539: The cellular level, the dephosphorylation of ATPases determines the flow of ions into and out of the cell. Proton pump inhibitors are a class of drug that acts directly on ATPases of the gastrointestinal tract. Other molecules besides ATP undergo dephosphorylation as part of other biological systems. Different compounds produce different free energy changes as a result of dephosphorylation. Psilocybin also relies on dephosphorylation to be metabolized into psilocin and further eliminated. No information on psilocybin's effect on
2464-441: The cerebellum. Dephosphorylation In biochemistry , dephosphorylation is the removal of a phosphate ( PO 3− 4 ) group from an organic compound by hydrolysis . It is a reversible post-translational modification . Dephosphorylation and its counterpart, phosphorylation , activate and deactivate enzymes by detaching or attaching phosphoric esters and anhydrides . A notable occurrence of dephosphorylation
2520-430: The change in free energy is currently available. The first protein complex of the photosynthesis component light-dependent reactions is referred to as photosystem II . The complex utilizes an enzyme to capture photons of light, providing the greater photosynthesis process with all of the electrons needed to produce ATP. Photosystem II is particularly temperature sensitive, and desphosphorylation has been implicated as
2576-582: The contrary, an overexpression of the PTPN22, but not the catalytically inactive PTPN22, increases motility of migrating T cells. An association of the PTPN22, but not its disease associated mutant form, with the LFA-1 results in a decreased LFA-1 clustering and a decreased adhesion. The role of the PTPN22 in the regulation of LFA-1-mediated adhesion and motility is also supported by the observation of increased LFA-1 expression in PTPN22 Treg cells. The C-terminal part of
2632-535: The effector/memory T cells, PTPN22-deficient mice contain a bigger amount of Treg cells in lymph nodes and spleens and this difference is more visible with increasing age of mice. There is also a change of the effector Treg cells : central Treg cells ratio in favor of the effector Treg cells. Influence of the PTPN22 deficiency on Treg cells number is consistent with the higher expression of PTPN22 in Treg cells than in naive T cells. Another abnormality of PTPN22-deficient mice
2688-510: The hydroxyl. Both processes are reversible and either mechanism can be used to activate or deactivate a protein. Phosphorylation of a protein produces many biochemical effects, such as changing its conformation to alter its binding to a specific ligand to increase or reduce its activity. Phosphorylation and dephosphorylation can be used on all types of substrates, such as structural proteins, enzymes, membrane channels, signaling molecules, and other kinases and phosphatases. The sum of these processes
2744-437: The protein synthesis apparatus also undergo phosphorylation and dephosphorylation and thus regulate the rates of protein synthesis. As part of posttranslational modifications, phosphate groups may be removed from serine, threonine, or tyrosine. As such, pathways of intracellular signal transduction depend on sequential phosphorylation and dephosphorylation of a wide variety of proteins. Adenosine triphosphate , or ATP, acts as
2800-497: The protein tyrosine phosphatase family can be found in the template at the bottom of this article. 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
2856-438: 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 . Together with tyrosine kinases , PTPs regulate
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#17330862107542912-565: The reversible nature of phosphorylation and dephosphorylation has been associated with a broad range of functional proteins, primarily enzymatic, but also including nonenzymatic proteins. Edwin Krebs and Edmond Fischer won the 1992 Nobel Prize in Physiology or Medicine for the discovery of reversible protein phosphorylation. Phosphorylation and dephosphorylation of hydroxyl groups belonging to neutral but polar amino acids such as serine, threonine, and tyrosine within specific target proteins
2968-438: The serine residue of phosphorylase to convert it from its b to a form via phosphorylation. Subsequently, Krebs and Fischer showed that this phosphorylation is part of a kinase cascade. Finally, after purifying the phosphorylated form of the enzyme, phosphorylase a , from rabbit liver, ion exchange chromatography was used to identify phosphoprotein phosphatase I and II. Since the discovery of these dephosphorylating proteins,
3024-407: The treatment of diabetes, sulfonylurea drugs are able to stimulate dephosphorylation of the glucose transporter GLUT4 , decreasing insulin resistance and increasing and glucose utilization. Dephosphorylation can play a key role in molecular biology, particularly cloning using restriction enzymes . The cut ends of a vector may re-ligate during a ligation step due to phosphorylation. By using
3080-443: Was confirmed by more robust meta-analysis . On the other hand, this allele is not linked to autoimmune diseases like multiple sclerosis , Ulcerative colitis , pephigus vulgaris and others. The exact way how the function of the PTPN22 is influenced by this mutation is still unknown. Throughout past years there were appearing evidences supporting that C1858T mutation is a loss-of-function mutation, but also evidences supporting that it
3136-471: Was then confirmed by other studies. In addition, C1858T allele of PTPN22 is associated with other autoimmune diseases including Rheumatoid arthritis , systemic lupus erythematosus , juvenile idiopathic arthritis , anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis , Graves’ disease , myasthenia gravis , Addison's disease . The contribution of the C1858T PTPN22 allele to those diseases
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