Serine/threonine-specific protein kinase

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Protein-serine/threonine kinases
Protein AURKA PDB 1mq4.png
Human Aurora Kinase PDB 1mq4 [1]
Identifiers
EC no. 2.7.11.-
CAS no. 9026-43-1
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serine L-Serin - L-Serine.svg
serine
threonine L-Threonin - L-Threonine.svg
threonine
phosphate Phosphate Group.svg
phosphate
phosphoserine L-Phosphoserine.png
phosphoserine

A serine/threonine protein kinase (EC 2.7.11.-) is a kinase enzyme, in particular a protein kinase, that phosphorylates the OH group of the amino-acid residues serine or threonine, which have similar side chains. At least 350 of the 500+ human protein kinases are serine/threonine kinases (STK). [2]

Contents

In enzymology, the term serine/threonine protein kinase describes a class of enzymes in the family of transferases, that transfer phosphates to the oxygen atom of a serine or threonine side chain in proteins. This process is called phosphorylation. Protein phosphorylation in particular plays a significant role in a wide range of cellular processes and is a very important post-translational modification. [3] [4] [5] [6] [7] [8] [9]

The chemical reaction performed by these enzymes can be written as

ATP + a protein ADP + a phosphoprotein

Thus, the two substrates of this enzyme are ATP and a protein, whereas its two products are ADP and phosphoprotein.

The systematic name of this enzyme class is ATP:protein phosphotransferase (non-specific).

Function

Serine/threonine kinases play a role in the regulation of cell proliferation, programmed cell death (apoptosis), cell differentiation, and embryonic development.[ citation needed ]

Selectivity

While serine/threonine kinases all phosphorylate serine or threonine residues in their substrates, they select specific residues to phosphorylate on the basis of residues that flank the phosphoacceptor site, which together comprise the consensus sequence . Since the consensus sequence residues of a target substrate only make contact with several key amino acids within the catalytic cleft of the kinase (usually through hydrophobic forces and ionic bonds), a kinase is usually not specific to a single substrate, but instead can phosphorylate a whole "substrate family" which share common recognition sequences. While the catalytic domain of these kinases is highly conserved, the sequence variation that is observed in the kinome (the subset of genes in the genome that encode kinases) provides for recognition of distinct substrates. Many kinases are inhibited by a pseudosubstrate that binds to the kinase like a real substrate but lacks the amino acid to be phosphorylated. When the pseudosubstrate is removed, the kinase can perform its normal function.[ citation needed ]

EC numbers

Many serine/threonine protein kinases do not have their own individual EC numbers and use 2.7.11.1, "non-specific serine/threonine protein kinase". This entry is for any enzyme that phosphorylates proteins while converting ATP to ADP (i.e., ATP:protein phosphotransferases.) [10] 2.7.11.37 "protein kinase" was the former generic placeholder and was split into several entries (including 2.7.11.1) in 2005. [11] 2.7.11.70 "protamine kinase" was merged into 2.7.11.1 in 2004. [12]

2.7.11.- is the generic level where all serine/threonine kinases should sit in. [13]

Types

Types include those acting directly as membrane-bound receptors (Receptor protein serine/threonine kinase) and intracellular kinases participating in Signal transduction. Of the latter, types include:

EC numberNameDescription
EC 2.7.11.1 CK2, also known by the misnomer casein kinase 2 was discovered in 1954 by Burnett and Kennedy.
EC 2.7.11.1 Mos/Raf kinasesform part of the MAPKK Kinase family and are activated by growth factors. The enzyme functions to stimulate growth of cells. Raf inhibition has become the target for new anti-metastatic cancer drugs as they inhibit the MAPK cascade and reduce cell proliferation.
EC 2.7.11.1 Protein Kinase B, also known as AKT kinaseThe v-akt gene was identified as the oncogene of retrovirus AKT8. The gene codes for a protein kinase. Human homologs of the AKT8 oncogenic protein were identified in 1987.By 1995 it had been found that Akt kinases function as mitogen-activated kinases downstream from cell surface receptors that activate phosphoinositide 3-kinase. Three human akt genes exist. All three Akt kinases regulate cell proliferation and Akt2 is particularly important for insulin actions in cells. A major target of Akt kinases is glycogen synthase kinase-3.
EC 2.7.11.1 Pelle is a serine/threonine kinase that can phosphorylate itself, and also Tube and Toll.
EC 2.7.11.11 Protein kinase A consists of two domains, a small domain with several β sheet structures and a larger domain containing several α helices. The binding sites for substrate and ATP are located in the catalytic cleft between the domains (or lobes). When ATP and substrate bind, the two lobes rotate so that the terminal phosphate group of the ATP and the target amino acid of the substrate move into the correct positions for the catalytic reaction to take place.
EC 2.7.11.13 Protein kinase C ('PKC')is actually a family of protein kinases consisting of ~10 isozymes. They are divided into three subfamilies: conventional (or classical), novel, and atypical based on their second messenger requirements.
EC 2.7.11.24 Mitogen-activated protein kinases (MAPKs)respond to extracellular stimuli (mitogens) and regulate various cellular activities, such as gene expression, mitosis, differentiation, and cell survival/apoptosis.
EC 2.7.11.17 Ca2+/calmodulin-dependent protein kinases or CaM kinases (CAMK)are primarily regulated by the Ca2+/calmodulin complex.
EC 2.7.11.19 Phosphorylase kinase was in fact, the first Ser/Thr protein kinase to be discovered (in 1959 by Krebs et al.).

Clinical significance

Serine/threonine kinase (STK) expression is altered in many types of cancer. [14] Limited benefit of serine/threonine kinase inhibitors has been demonstrated in ovarian cancer [15] but studies are ongoing to evaluate their safety and efficacy.[ citation needed ]

Serine/threonine protein kinase p90-kDa ribosomal S6 kinase (RSK) is in involved in development of some prostate cancers. [16]

Raf inhibition has become the target for new anti-metastatic cancer drugs as they inhibit the MAPK cascade and reduce cell proliferation.[ citation needed ]

See also

Related Research Articles

<span class="mw-page-title-main">Protein kinase</span> Enzyme that adds phosphate groups to other proteins

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.

<span class="mw-page-title-main">Kinase</span> Enzyme catalyzing transfer of phosphate groups onto specific substrates

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. As a result, kinase 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 C, commonly abbreviated to PKC (EC 2.7.11.13), is a family of protein kinase enzymes that are involved in controlling the function of other proteins through the phosphorylation of hydroxyl groups of serine and threonine amino acid residues on these proteins, or a member of this family. PKC enzymes in turn are activated by signals such as increases in the concentration of diacylglycerol (DAG) or calcium ions (Ca2+). Hence PKC enzymes play important roles in several signal transduction cascades.

The IκB kinase is an enzyme complex that is involved in propagating the cellular response to inflammation, specifically the regulation of lymphocytes.

<span class="mw-page-title-main">BRAF (gene)</span> Protein-coding gene in humans

BRAF is a human gene that encodes a protein called B-Raf. The gene is also referred to as proto-oncogene B-Raf and v-Raf murine sarcoma viral oncogene homolog B, while the protein is more formally known as serine/threonine-protein kinase B-Raf.

In enzymology, a [3-methyl-2-oxobutanoate dehydrogenase (acetyl-transferring)] is an enzyme that catalyzes the chemical reaction

In enzymology, a [acetyl-CoA carboxylase] kinase is an enzyme that catalyzes the chemical reaction

In enzymology, a beta-adrenergic-receptor kinase is an enzyme that catalyzes the chemical reaction:

In enzymology, a dephospho-[reductase kinase] kinase is an enzyme that catalyzes the chemical reaction

In enzymology, an elongation factor 2 kinase is an enzyme that catalyzes the chemical reaction:

In enzymology, a [isocitrate dehydrogenase (NADP+)] kinase (EC 2.7.11.5) is an enzyme that catalyzes the chemical reaction:

<span class="mw-page-title-main">Kanamycin kinase</span>

Aminoglycoside-3'-phosphotransferase, also known as aminoglycoside kinase, is an enzyme that primarily catalyzes the addition of phosphate from ATP to the 3'-hydroxyl group of a 4,6-disubstituted aminoglycoside, such as kanamycin. However, APH(3') has also been found to phosphorylate at the 5'-hydroxyl group in 4,5-disubstituted aminoglycosides, which lack a 3'-hydroxyl group, and to diphosphorylate hydroxyl groups in aminoglycosides that have both 3'- and 5'-hydroxyl groups. Primarily positively charged at biological conditions, aminoglycosides bind to the negatively charged backbone of nucleic acids to disrupt protein synthesis, effectively inhibiting bacterial cell growth. APH(3') mediated phosphorylation of aminoglycosides effectively disrupts their mechanism of action, introducing a phosphate group that reduces their binding affinity due to steric hindrances and unfavorable electrostatic interactions. APH(3') is primarily found in certain species of gram-positive bacteria.

In enzymology, a low-density-lipoprotein receptor kinase is an enzyme that catalyzes the chemical reaction

In enzymology, a myosin-heavy-chain kinase is an enzyme that catalyzes the chemical reaction

In enzymology, a polo kinase is a kinase enzyme i.e. one that catalyzes the chemical reaction

<span class="mw-page-title-main">Tau-protein kinase</span> Class of enzymes

In enzymology, a tau-protein kinase is an enzyme that catalyzes the chemical reaction

In enzymology, a tropomyosin kinase is an enzyme that catalyzes the chemical reaction

In enzymology, a [tyrosine 3-monooxygenase] kinase is an enzyme that catalyzes the chemical reaction

<span class="mw-page-title-main">Protein phosphorylation</span> Process of introducing a phosphate group on to a protein

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 activated, deactivated, or otherwise modifying its function. Approximately 13,000 human proteins have sites that are phosphorylated.

References

  1. ↑ Nowakowski, J.; Cronin, C. N.; McRee, D. E.; Knuth, M. W.; Nelson, C. G.; Pavletich, N. P.; Rogers, J.; Sang, B. C.; Scheibe, D. N.; Swanson, R. V.; Thompson, D. A. (2002). "Structures of the cancer-related Aurora-A, FAK, and EphA2 protein kinases from nanovolume crystallography". Structure. 10 (12): 1659–1667. doi: 10.1016/S0969-2126(02)00907-3 . PMID   12467573.
  2. ↑ Modi, V; Dunbrack, RL (24 December 2019). "A Structurally-Validated Multiple Sequence Alignment of 497 Human Protein Kinase Domains". Scientific Reports. 9 (1): 19790. Bibcode:2019NatSR...919790M. doi:10.1038/s41598-019-56499-4. PMC   6930252 . PMID   31875044.
  3. ↑ Damuni Z, Reed LJ (1988). "Purification and properties of a protamine kinase and a type II casein kinase from bovine kidney mitochondria". Arch. Biochem. Biophys. 262 (2): 574–84. doi:10.1016/0003-9861(88)90408-0. PMID   2835010.
  4. ↑ Baggio B, Pinna LA, Moret V, Siliprandi N (1970). "A simple procedure for the purification of rat liver phosvitin kinase". Biochim. Biophys. Acta. 212 (3): 515–7. doi:10.1016/0005-2744(70)90261-5. PMID   5456997.
  5. ↑ Jergil B, Dixon GH (1970). "Protamine kinase from rainbow trout testis. Partial purification and characterization". J. Biol. Chem. 245 (2): 425–34. doi: 10.1016/S0021-9258(18)63408-8 . PMID   4312674.
  6. ↑ Langan TA (1969). "Action of adenosine 3',5'-monophosphate-dependent histone kinase in vivo". J. Biol. Chem. 244 (20): 5763–5. doi: 10.1016/S0021-9258(18)63626-9 . PMID   4310608.
  7. ↑ Takeuchi M, Yanagida M (1993). "A mitotic role for a novel fission yeast protein kinase dsk1 with cell cycle stage dependent phosphorylation and localization". Mol. Biol. Cell. 4 (3): 247–60. doi:10.1091/mbc.4.3.247. PMC   300923 . PMID   8485317.
  8. ↑ NF; Lützelberger, M; Weigmann, H; Klingenhoff, A; Shenoy, S; Käufer, NF (1997). "Functional analysis of the fission yeast Prp4 protein kinase involved in pre-mRNA splicing and isolation of a putative mammalian homologue". Nucleic Acids Res. 25 (5): 1028–35. doi:10.1093/nar/25.5.1028. PMC   146536 . PMID   9102632.
  9. ↑ Wang Y, Hofmann TG, Runkel L, Haaf T, Schaller H, Debatin K, Hug H (2001). "Isolation and characterization of cDNAs for the protein kinase HIPK2". Biochim. Biophys. Acta. 1518 (1–2): 168–72. doi:10.1016/S0167-4781(00)00308-0. PMID   11267674.
  10. ↑ "ENZYME - 2.7.11.1 non-specific serine/threonine protein kinase". enzyme.expasy.org. Retrieved 2023-12-25.
  11. ↑ "KEGG ENZYME: 2.7.1.37". www.genome.jp. Retrieved 2023-12-25.
  12. ↑ "KEGG ENZYME: 2.7.1.70". www.genome.jp. Retrieved 2023-12-25.
  13. ↑ "EC 2.7.11". iubmb.qmul.ac.uk. Retrieved 2023-12-25.
  14. ↑ Capra, Maria; Nuciforo, Paolo Giovanni; Confalonieri, Stefano; Quarto, Micaela; Bianchi, Marco; Nebuloni, Manuela; Boldorini, Renzo; Pallotti, Francesco; Viale, Giuseppe; Gishizky, Mikhail L.; Draetta, Giulio F.; Fiore, Pier Paolo Di (15 August 2006). "Frequent Alterations in the Expression of Serine/Threonine Kinases in Human Cancers". Cancer Research. 66 (16): 8147–8154. doi:10.1158/0008-5472.CAN-05-3489. PMID   16912193.
  15. ↑ Ciccone, Marcia A.; Maoz, Asaf; Casabar, Jennifer K.; Machida, Hiroko; Mabuchi, Seiji; Matsuo, Koji (2 July 2016). "Clinical outcome of treatment with serine-threonine kinase inhibitors in recurrent epithelial ovarian cancer: a systematic review of literature". Expert Opinion on Investigational Drugs. 25 (7): 781–796. doi:10.1080/13543784.2016.1181748. PMC   7534810 . PMID   27101098.
  16. ↑ Clark, D. E.; Errington, T. M.; Smith, J. A.; Frierson, H. F.; Weber, M. J.; Lannigan, D. A. (15 April 2005). "The Serine/Threonine Protein Kinase, p90 Ribosomal S6 Kinase, Is an Important Regulator of Prostate Cancer Cell Proliferation". Cancer Research. 65 (8): 3108–3116. doi:10.1158/0008-5472.CAN-04-3151. PMID   15833840.
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