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A protein kinase is a kinase which selectively modifies other proteins by covalently adding phosphates to them (phosphorylation) as opposed to kinases which modify lipids, carbohydrates, or other molecules. Phosphorylation usually results in a functional change of the target protein (substrate) by changing enzyme activity, cellular location, or association with other proteins. The human genome contains about 500 protein kinase genes and they constitute about 2% of all human genes. There are two main types of protein kinase. The great majority are serine/threonine kinases, which phosphorylate the hydroxyl groups of serines and threonines in their targets. Most of the others are tyrosine kinases, although additional types exist. Protein kinases are also found in bacteria and plants. Up to 30% of all human proteins may be modified by kinase activity, and kinases are known to regulate the majority of cellular pathways, especially those involved in signal transduction.
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.
In biochemistry, a kinase is an enzyme that catalyzes the transfer of phosphate groups from high-energy, phosphate-donating molecules to specific substrates. This process is known as phosphorylation, where the high-energy ATP molecule donates a phosphate group to the substrate molecule. This transesterification produces a phosphorylated substrate and ADP. Conversely, it is referred to as dephosphorylation when the phosphorylated substrate donates a phosphate group and ADP gains a phosphate group. These two processes, phosphorylation and dephosphorylation, occur four times during glycolysis.
In cell biology, protein kinase A (PKA) is a family of enzymes whose activity is dependent on cellular levels of cyclic AMP (cAMP). PKA is also known as cAMP-dependent protein kinase. PKA has several functions in the cell, including regulation of glycogen, sugar, and lipid metabolism. It should not be confused with 5'-AMP-activated protein kinase.
In biochemistry, a phosphatase is an enzyme that uses water to cleave a phosphoric acid monoester into a phosphate ion and an alcohol. Because a phosphatase enzyme catalyzes the hydrolysis of its substrate, it is a subcategory of hydrolases. Phosphatase enzymes are essential to many biological functions, because phosphorylation and dephosphorylation serve diverse roles in cellular regulation and signaling. Whereas phosphatases remove phosphate groups from molecules, kinases catalyze the transfer of phosphate groups to molecules from ATP. Together, kinases and phosphatases direct a form of post-translational modification that is essential to the cell's regulatory network.
In biochemistry, dephosphorylation is the removal of a phosphate (PO43−) 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 is the conversion of ATP to ADP and inorganic phosphate.
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:
Receptor tyrosine kinases (RTKs) are the high-affinity cell surface receptors for many polypeptide growth factors, cytokines, and hormones. Of the 90 unique tyrosine kinase genes identified in the human genome, 58 encode receptor tyrosine kinase proteins. Receptor tyrosine kinases have been shown not only to be key regulators of normal cellular processes but also to have a critical role in the development and progression of many types of cancer. Mutations in receptor tyrosine kinases lead to activation of a series of signalling cascades which have numerous effects on protein expression. Receptor tyrosine kinases are part of the larger family of protein tyrosine kinases, encompassing the receptor tyrosine kinase proteins which contain a transmembrane domain, as well as the non-receptor tyrosine kinases which do not possess transmembrane domains.
In molecular biology, biochemistry and cell signaling the kinome of an organism is the complete set of protein kinases encoded in its genome. Kinases are usually enzymes that catalyze phosphorylation reactions and fall into several groups and families, e.g., those that phosphorylate the amino acids serine and threonine, those that phosphorylate tyrosine and some that can phosphorylate both, such as the MAP2K and GSK families. The term was first used in 2002 by Gerard Manning and colleagues in twin papers analyzing the 518 human protein kinases, and refers to both protein kinases and protein pseudokinases and their evolution of protein kinases throughout the eukaryotes. Other kinomes have been determined for rice, several fungi, nematodes, and insects, sea urchins, Dictyostelium discoideum, and the process of infection by Mycobacterium tuberculosis. Although the primary sequence of protein kinases shows substantial divergence between unrelated eukaryotes, and amino acid differences in catalytic motifs have permitted their separation of kinomes into canonical and pseudokinase subtypes, the variation found in the amino acid motifs adjacent to the site of actual phosphorylation of substrates by eukaryotic kinases is much smaller.
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.
M-phase inducer phosphatase 1 also known as dual specificity phosphatase Cdc25A is a protein that in humans is encoded by the cell division cycle 25 homolog A (CDC25A) gene.
Protein phosphorylation is a reversible post-translational modification of proteins in which an amino acid residue is phosphorylated by a protein kinase by the addition of a covalently bound phosphate group. Phosphorylation alters the structural conformation of a protein, causing it to become either activated or deactivated, or otherwise modifying its function. Approximately 13000 human proteins have sites that are phosphorylated.
Receptor-type tyrosine-protein phosphatase T is an enzyme that in humans is encoded by the PTPRT gene.
Autophosphorylation is a type of post-translational modification of proteins. It is generally defined as the phosphorylation of the kinase by itself. In eukaryotes, this process occurs by the addition of a phosphate group to serine, threonine or tyrosine residues within protein kinases, normally to regulate the catalytic activity. Autophosphorylation may occur when a kinases' own active site catalyzes the phosphorylation reaction, or when another kinase of the same type provides the active site that carries out the chemistry. The latter often occurs when kinase molecules dimerize. In general, the phosphate groups introduced are gamma phosphates from nucleoside triphosphates, most commonly ATP.
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.
Protein Arginine Phosphatase (PAPs), also known as Phosphoarginine Phosphatase, is an enzyme that catalyzes the dephosphorylation of phosphoarginine residues in proteins. Protein phosphatases (PPs) are "obligatory heteromers" made up of two maximum catalytic subunits attached to a non-catalytic subunit. Arginine modification is a post-translational protein modification in gram-positive bacteria. McsB and YwIE were recently identified as phosphorylating enzymes in Bacillus Subtilis (B.Subtilis). YwIE was thought to be a protein-tyrosine-phosphatase, and McsB a tyrosine-kinase, however in 2012 Elsholz et al. showed that McsB is a protein-arginine-kinase (PAK) and YwlE is a phosphatase-arginine-phosphatase (PAP).
H3Y41P is an epigenetic modification to the DNA packaging protein histone H3. It is a mark that indicates the phosphorylation the 41st tyrosine residue of the histone H3 protein.
H3T45P is an epigenetic modification to the DNA packaging protein histone H3. It is a mark that indicates the phosphorylation the 45th threonine residue of the histone H3 protein.
H3T11P is an epigenetic modification to the DNA packaging protein histone H3. It is a mark that indicates the phosphorylation the 11th threonine residue of the histone H3 protein.
H3T3P is an epigenetic modification to the DNA packaging protein histone H3. It is a mark that indicates the phosphorylation the 3rd threonine residue of the histone H3 protein.
References
- 1 2 3 4 Mark J. Chen, Jack E. Dixon & Gerard Manning (2017). "Genomics and evolution of protein phosphatases". Science Signaling . 10 (474): eaag1796. doi:10.1126/scisignal.aag1796. PMID 28400531. S2CID 41041971.
- ↑ Rachel Brenchley, Humera Tariq, Helen McElhinney, Balazs Szoor, Julie Huxley-Jones, Robert David Stevens, Keith Matthews & Lydia Tabernero (2007). "The TriTryp phosphatome: analysis of the protein phosphatase catalytic domains". BMC Genomics . 8: 434. doi:10.1186/1471-2164-8-434. PMC 2175518 . PMID 18039372.
{{cite journal}}: CS1 maint: multiple names: authors list (link) - ↑ Jonathan M. Wilkes & Christian Doerig (2008). "The protein-phosphatome of the human malaria parasite Plasmodium falciparum". BMC Genomics . 9: 412. doi:10.1186/1471-2164-9-412. PMC 2559854 . PMID 18793411.
- ↑ Tamanna Anwar & Samudrala Gourinath (2016). "Deep Insight into the Phosphatomes of Parasitic Protozoa and a Web Resource ProtozPhosDB". PLoS ONE . 11 (12): e0167594. Bibcode:2016PLoSO..1167594A. doi: 10.1371/journal.pone.0167594 . PMC 5145157 . PMID 27930683.
- ↑ Yingzi Yun, Zunyong Liu, Yanni Yin, Jinhua Jiang, Yun Chen, Jin-Rong Xu & Zhonghua Ma (2015). "Functional analysis of the Fusarium graminearum phosphatome". The New Phytologist. 207 (1): 119–134. doi: 10.1111/nph.13374 . PMID 25758923.
{{cite journal}}: CS1 maint: multiple names: authors list (link) - ↑ David S. Guttery, Benoit Poulin, Abhinay Ramaprasad, Richard J. Wall, David J. P. Ferguson, Declan Brady, Eva-Maria Patzewitz, Sarah Whipple, Ursula Straschil, Megan H. Wright, Alyaa M. A. H. Mohamed, Anand Radhakrishnan, Stefan T. Arold, Edward W. Tate, Anthony A. Holder, Bill Wickstead, Arnab Pain & Rita Tewari (2014). "Genome-wide functional analysis of Plasmodium protein phosphatases reveals key regulators of parasite development and differentiation". Cell Host & Microbe . 16 (1): 128–140. doi:10.1016/j.chom.2014.05.020. PMC 4094981 . PMID 25011111.
{{cite journal}}: CS1 maint: multiple names: authors list (link) - ↑ Francesca Sacco, Pier Federico Gherardini, Serena Paoluzi, Julio Saez-Rodriguez, Manuela Helmer-Citterich, Antonella Ragnini-Wilson, Luisa Castagnoli & Gianni Cesareni (2012). "Mapping the human phosphatome on growth pathways". Molecular Systems Biology . 8: 603. doi:10.1038/msb.2012.36. PMC 3435503 . PMID 22893001.
{{cite journal}}: CS1 maint: multiple names: authors list (link) - ↑ Sofi G. Julien, Nadia Dube, Serge Hardy & Michel L. Tremblay (2011). "Inside the human cancer tyrosine phosphatome". Nature Reviews. Cancer . 11 (1): 35–49. doi:10.1038/nrc2980. PMID 21179176. S2CID 9743535.
{{cite journal}}: CS1 maint: multiple names: authors list (link) - ↑ Veronika Reiterer, Patrick A. Eyers & Hesso Farhan (2014). "Day of the dead: pseudokinases and pseudophosphatases in physiology and disease". Trends in Cell Biology . 24 (9): 489–505. doi:10.1016/j.tcb.2014.03.008. PMID 24818526.