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Protein kinase

February 27, 2023

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.[1] 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 and most of the others are tyrosine kinases, although additional types exist.[2] 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.

General scheme of kinase function

Chemical activity

 
Above is a ball-and-stick model of the inorganic phosphate molecule (HPO42−). Colour coding: P (orange); O (red); H (white).

The chemical activity of a protein kinase involves removing a phosphate group from ATP and covalently attaching it to one of three amino acids that have a free hydroxyl group. Most kinases act on both serine and threonine, others act on tyrosine, and a number (dual-specificity kinases) act on all three.[3] There are also protein kinases that phosphorylate other amino acids, including histidine kinases that phosphorylate histidine residues.[4]

Structure

Main article: Protein kinase domain

Eukaryotic protein kinases are enzymes that belong to a very extensive family of proteins that share a conserved catalytic core.[5][6][7][8] The structures of over 280 human protein kinases have been determined.[9]

There are a number of conserved regions in the catalytic domain of protein kinases. In the N-terminal extremity of the catalytic domain there is a glycine-rich stretch of residues in the vicinity of a lysine amino acid, which has been shown to be involved in ATP binding. In the central part of the catalytic domain, there is a conserved aspartic acid, which is important for the catalytic activity of the enzyme.[10]

Serine/threonine-specific protein kinases

 
Calcium/calmodulin-dependent protein kinase II (CaMKII) is an example of a serine/threonine-specific protein kinase.
Main article: Serine/threonine-specific protein kinases

Serine/threonine protein kinases (EC 2.7.11.1) phosphorylate the OH group of serine or threonine (which have similar side chains). Activity of these protein kinases can be regulated by specific events (e.g., DNA damage), as well as numerous chemical signals, including cAMP/cGMP, diacylglycerol, and Ca2+/calmodulin. One very important group of protein kinases are the MAP kinases (acronym from: "mitogen-activated protein kinases"). Important subgroups are the kinases of the ERK subfamily, typically activated by mitogenic signals, and the stress-activated protein kinases JNK and p38. While MAP kinases are serine/threonine-specific, they are activated by combined phosphorylation on serine/threonine and tyrosine residues. Activity of MAP kinases is restricted by a number of protein phosphatases, which remove the phosphate groups that are added to specific serine or threonine residues of the kinase and are required to maintain the kinase in an active conformation.

Tyrosine-specific protein kinases

Main article: Tyrosine kinase

Tyrosine-specific protein kinases (EC 2.7.10.1 and EC 2.7.10.2) phosphorylate tyrosine amino acid residues, and like serine/threonine-specific kinases are used in signal transduction. They act primarily as growth factor receptors and in downstream signaling from growth factors.[11] Some examples include:

Receptor tyrosine kinases

Main article: Receptor tyrosine kinase

These kinases consist of extracellular domains, a transmembrane spanning alpha helix, and an intracellular tyrosine kinase domain protruding into the cytoplasm. They play important roles in regulating cell division, cellular differentiation, and morphogenesis. More than 50 receptor tyrosine kinases are known in mammals.

Structure

The extracellular domains serve as the ligand-binding part of the molecule, often inducing the domains to form homo- or heterodimers. The transmembrane element is a single α helix. The intracellular or cytoplasmic Protein kinase domain is responsible for the (highly conserved) kinase activity, as well as several regulatory functions.

Regulation

Ligand binding causes two reactions:

  1. Dimerization of two monomeric receptor kinases or stabilization of a loose dimer. Many ligands of receptor tyrosine kinases are multivalent. Some tyrosine receptor kinases (e.g., the platelet-derived growth factor receptor) can form heterodimers with other similar but not identical kinases of the same subfamily, allowing a highly varied response to the extracellular signal.
  2. Trans-autophosphorylation (phosphorylation by the other kinase in the dimer) of the kinase.

Autophosphorylation stabilizes the active conformation of the kinase domain. When several amino acids suitable for phosphorylation are present in the kinase domain (e.g., the insulin-like growth factor receptor), the activity of the kinase can increase with the number of phosphorylated amino acids; in this case, the first phosphorylation switches the kinase from "off" to "standby".

Signal transduction

The active tyrosine kinase phosphorylates specific target proteins, which are often enzymes themselves. An important target is the ras protein signal-transduction chain.

Receptor-associated tyrosine kinases

Main article: Non-receptor tyrosine kinase

Tyrosine kinases recruited to a receptor following hormone binding are receptor-associated tyrosine kinases and are involved in a number of signaling cascades, in particular those involved in cytokine signaling (but also others, including growth hormone). One such receptor-associated tyrosine kinase is Janus kinase (JAK), many of whose effects are mediated by STAT proteins. (See JAK-STAT pathway.)

Dual-specificity protein kinases

Main article: Dual-specificity kinase

Some kinases have dual-specificity kinase activities. For example, MEK (MAPKK), which is involved in the MAP kinase cascade, is a both a serine/threonine and tyrosine kinase.

Histidine-specific protein kinases

Histidine kinases are structurally distinct from most other protein kinases and are found mostly in prokaryotes as part of two-component signal transduction mechanisms. A phosphate group from ATP is first added to a histidine residue within the kinase, and later transferred to an aspartate residue on a 'receiver domain' on a different protein, or sometimes on the kinase itself. The aspartyl phosphate residue is then active in signaling.

Histidine kinases are found widely in prokaryotes, as well as in plants, fungi and eukaryotes. The pyruvate dehydrogenase family of kinases in animals is structurally related to histidine kinases, but instead phosphorylate serine residues, and probably do not use a phospho-histidine intermediate.

Aspartic acid/glutamic acid-specific protein kinases

Inhibitors

Main article: Protein kinase inhibitor

Deregulated kinase activity is a frequent cause of disease, in particular cancer, wherein kinases regulate many aspects that control cell growth, movement and death. Drugs that inhibit specific kinases are being developed to treat several diseases, and some are currently in clinical use, including Gleevec (imatinib) and Iressa (gefitinib).

Kinase assays and profiling

Drug developments for kinase inhibitors are started from kinase assays, the lead compounds are usually profiled for specificity before moving into further tests. Many profiling services are available from fluorescent-based assays to , and competition binding assays.

References

  1. ^ Manning G, Whyte DB, Martinez R, Hunter T, Sudarsanam S (2002). "The protein kinase complement of the human genome". Science. 298 (5600): 1912–1934. Bibcode:2002Sci...298.1912M. doi:10.1126/science.1075762. PMID 12471243. S2CID 26554314.
  2. ^ Alberts, Bruce (18 November 2014). Molecular biology of the cell (Sixth ed.). New York. pp. 819–820. ISBN 978-0-8153-4432-2. OCLC 887605755.
  3. ^ Dhanasekaran N, Premkumar Reddy E (September 1998). "Signaling by dual specificity kinases". Oncogene. 17 (11 Reviews): 1447–55. doi:10.1038/sj.onc.1202251. PMID 9779990.
  4. ^ Besant PG, Tan E, Attwood PV (March 2003). "Mammalian protein histidine kinases". Int. J. Biochem. Cell Biol. 35 (3): 297–309. doi:10.1016/S1357-2725(02)00257-1. PMID 12531242.
  5. ^ Hanks SK (2003). "Genomic analysis of the eukaryotic protein kinase superfamily: a perspective". Genome Biol. 4 (5): 111. doi:10.1186/gb-2003-4-5-111. PMC 156577. PMID 12734000.
  6. ^ Hanks SK, Hunter T (May 1995). "Protein kinases 6. The eukaryotic protein kinase superfamily: kinase (catalytic) domain structure and classification". FASEB J. 9 (8): 576–96. doi:10.1096/fasebj.9.8.7768349. PMID 7768349. S2CID 21377422.
  7. ^ Hunter T (1991). "Protein kinase classification". Meth. Enzymol. Methods in Enzymology. 200: 3–37. doi:10.1016/0076-6879(91)00125-G. ISBN 9780121821012. PMID 1835513.
  8. ^ Hanks SK, Quinn AM (1991). "Protein kinase catalytic domain sequence database: identification of conserved features of primary structure and classification of family members". Meth. Enzymol. Methods in Enzymology. 200: 38–62. doi:10.1016/0076-6879(91)00126-H. ISBN 9780121821012. PMID 1956325.
  9. ^ Modi, V; Dunbrack, RL (2019-12-24). "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.
  10. ^ Knighton DR, Zheng JH, Ten Eyck LF, Ashford VA, Xuong NH, Taylor SS, Sowadski JM (July 1991). "Crystal structure of the catalytic subunit of cyclic adenosine monophosphate-dependent protein kinase". Science. 253 (5018): 407–14. Bibcode:1991Sci...253..407K. doi:10.1126/science.1862342. PMID 1862342.
  11. ^ Higashiyama S, Iwabuki H, Morimoto C, Hieda M, Inoue H, Matsushita N. Membrane-anchored growth factors, the epidermal growth factor family: beyond receptor ligands. Cancer Sci. 2008 Feb;99(2):214-20. Review. PMID: 18271917
  12. ^ Carpenter G. The EGF receptor: a nexus for trafficking and signaling. Bioessays. 2000 Aug;22(8):697-707. Review. PMID: 10918300

External links

  • Human and mouse protein kinases in UniProt: classification and index
  • Kinase.Com: Genomics, evolution and large-scale analysis of protein kinases (non-commercial).
  • KinMutBase: A registry of disease-causing mutations in protein kinase domains
  • KLIFS (Kinase-Ligand Interaction Fingerprints and Structures) Database -- analysis of kinase structures and kinase-inhibitor interactions
  • KinCore: the Kinase Conformation Resource: A web resource for protein kinase sequence, structure and phylogeny
  • Kinomer: A multilevel HMM library for the classification and functional annotation of eukaryotic protein kinases.

February 27, 2023
protein, kinase, protein, kinase, kinase, which, selectively, modifies, other, proteins, covalently, adding, phosphates, them, phosphorylation, opposed, kinases, which, modify, lipids, carbohydrates, other, molecules, phosphorylation, usually, results, functio. 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 1 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 and most of the others are tyrosine kinases although additional types exist 2 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 General scheme of kinase function Contents 1 Chemical activity 2 Structure 3 Serine threonine specific protein kinases 4 Tyrosine specific protein kinases 4 1 Receptor tyrosine kinases 4 1 1 Structure 4 1 2 Regulation 4 1 3 Signal transduction 4 2 Receptor associated tyrosine kinases 5 Dual specificity protein kinases 6 Histidine specific protein kinases 7 Aspartic acid glutamic acid specific protein kinases 8 Inhibitors 9 Kinase assays and profiling 10 References 11 External linksChemical activity Edit Above is a ball and stick model of the inorganic phosphate molecule HPO42 Colour coding P orange O red H white The chemical activity of a protein kinase involves removing a phosphate group from ATP and covalently attaching it to one of three amino acids that have a free hydroxyl group Most kinases act on both serine and threonine others act on tyrosine and a number dual specificity kinases act on all three 3 There are also protein kinases that phosphorylate other amino acids including histidine kinases that phosphorylate histidine residues 4 Structure EditMain article Protein kinase domain Eukaryotic protein kinases are enzymes that belong to a very extensive family of proteins that share a conserved catalytic core 5 6 7 8 The structures of over 280 human protein kinases have been determined 9 There are a number of conserved regions in the catalytic domain of protein kinases In the N terminal extremity of the catalytic domain there is a glycine rich stretch of residues in the vicinity of a lysine amino acid which has been shown to be involved in ATP binding In the central part of the catalytic domain there is a conserved aspartic acid which is important for the catalytic activity of the enzyme 10 Serine threonine specific protein kinases Edit Calcium calmodulin dependent protein kinase II CaMKII is an example of a serine threonine specific protein kinase Main article Serine threonine specific protein kinases Serine threonine protein kinases EC 2 7 11 1 phosphorylate the OH group of serine or threonine which have similar side chains Activity of these protein kinases can be regulated by specific events e g DNA damage as well as numerous chemical signals including cAMP cGMP diacylglycerol and Ca2 calmodulin One very important group of protein kinases are the MAP kinases acronym from mitogen activated protein kinases Important subgroups are the kinases of the ERK subfamily typically activated by mitogenic signals and the stress activated protein kinases JNK and p38 While MAP kinases are serine threonine specific they are activated by combined phosphorylation on serine threonine and tyrosine residues Activity of MAP kinases is restricted by a number of protein phosphatases which remove the phosphate groups that are added to specific serine or threonine residues of the kinase and are required to maintain the kinase in an active conformation Tyrosine specific protein kinases EditMain article Tyrosine kinase Tyrosine specific protein kinases EC 2 7 10 1 and EC 2 7 10 2 phosphorylate tyrosine amino acid residues and like serine threonine specific kinases are used in signal transduction They act primarily as growth factor receptors and in downstream signaling from growth factors 11 Some examples include Platelet derived growth factor receptor PDGFR Epidermal growth factor receptor EGFR 12 Insulin receptor and insulin like growth factor 1 receptor IGF1R Stem cell factor SCF receptor also called c kit see the article on gastrointestinal stromal tumor Receptor tyrosine kinases Edit Main article Receptor tyrosine kinase These kinases consist of extracellular domains a transmembrane spanning alpha helix and an intracellular tyrosine kinase domain protruding into the cytoplasm They play important roles in regulating cell division cellular differentiation and morphogenesis More than 50 receptor tyrosine kinases are known in mammals Structure Edit The extracellular domains serve as the ligand binding part of the molecule often inducing the domains to form homo or heterodimers The transmembrane element is a single a helix The intracellular or cytoplasmic Protein kinase domain is responsible for the highly conserved kinase activity as well as several regulatory functions Regulation Edit Ligand binding causes two reactions Dimerization of two monomeric receptor kinases or stabilization of a loose dimer Many ligands of receptor tyrosine kinases are multivalent Some tyrosine receptor kinases e g the platelet derived growth factor receptor can form heterodimers with other similar but not identical kinases of the same subfamily allowing a highly varied response to the extracellular signal Trans autophosphorylation phosphorylation by the other kinase in the dimer of the kinase Autophosphorylation stabilizes the active conformation of the kinase domain When several amino acids suitable for phosphorylation are present in the kinase domain e g the insulin like growth factor receptor the activity of the kinase can increase with the number of phosphorylated amino acids in this case the first phosphorylation switches the kinase from off to standby Signal transduction Edit The active tyrosine kinase phosphorylates specific target proteins which are often enzymes themselves An important target is the ras protein signal transduction chain Receptor associated tyrosine kinases Edit Main article Non receptor tyrosine kinase Tyrosine kinases recruited to a receptor following hormone binding are receptor associated tyrosine kinases and are involved in a number of signaling cascades in particular those involved in cytokine signaling but also others including growth hormone One such receptor associated tyrosine kinase is Janus kinase JAK many of whose effects are mediated by STAT proteins See JAK STAT pathway Dual specificity protein kinases EditMain article Dual specificity kinase Some kinases have dual specificity kinase activities For example MEK MAPKK which is involved in the MAP kinase cascade is a both a serine threonine and tyrosine kinase Histidine specific protein kinases EditHistidine kinases are structurally distinct from most other protein kinases and are found mostly in prokaryotes as part of two component signal transduction mechanisms A phosphate group from ATP is first added to a histidine residue within the kinase and later transferred to an aspartate residue on a receiver domain on a different protein or sometimes on the kinase itself The aspartyl phosphate residue is then active in signaling Histidine kinases are found widely in prokaryotes as well as in plants fungi and eukaryotes The pyruvate dehydrogenase family of kinases in animals is structurally related to histidine kinases but instead phosphorylate serine residues and probably do not use a phospho histidine intermediate Aspartic acid glutamic acid specific protein kinases EditThis section needs expansion You can help by adding to it June 2008 Inhibitors EditMain article Protein kinase inhibitor Deregulated kinase activity is a frequent cause of disease in particular cancer wherein kinases regulate many aspects that control cell growth movement and death Drugs that inhibit specific kinases are being developed to treat several diseases and some are currently in clinical use including Gleevec imatinib and Iressa gefitinib Anthra 1 9 cd pyrazol 6 2H one StaurosporineKinase assays and profiling EditDrug developments for kinase inhibitors are started from kinase assays the lead compounds are usually profiled for specificity before moving into further tests Many profiling services are available from fluorescent based assays to radioisotope based detections and competition binding assays References Edit Manning G Whyte DB Martinez R Hunter T Sudarsanam S 2002 The protein kinase complement of the human genome Science 298 5600 1912 1934 Bibcode 2002Sci 298 1912M doi 10 1126 science 1075762 PMID 12471243 S2CID 26554314 Alberts Bruce 18 November 2014 Molecular biology of the cell Sixth ed New York pp 819 820 ISBN 978 0 8153 4432 2 OCLC 887605755 Dhanasekaran N Premkumar Reddy E September 1998 Signaling by dual specificity kinases Oncogene 17 11 Reviews 1447 55 doi 10 1038 sj onc 1202251 PMID 9779990 Besant PG Tan E Attwood PV March 2003 Mammalian protein histidine kinases Int J Biochem Cell Biol 35 3 297 309 doi 10 1016 S1357 2725 02 00257 1 PMID 12531242 Hanks SK 2003 Genomic analysis of the eukaryotic protein kinase superfamily a perspective Genome Biol 4 5 111 doi 10 1186 gb 2003 4 5 111 PMC 156577 PMID 12734000 Hanks SK Hunter T May 1995 Protein kinases 6 The eukaryotic protein kinase superfamily kinase catalytic domain structure and classification FASEB J 9 8 576 96 doi 10 1096 fasebj 9 8 7768349 PMID 7768349 S2CID 21377422 Hunter T 1991 Protein kinase classification Meth Enzymol Methods in Enzymology 200 3 37 doi 10 1016 0076 6879 91 00125 G ISBN 9780121821012 PMID 1835513 Hanks SK Quinn AM 1991 Protein kinase catalytic domain sequence database identification of conserved features of primary structure and classification of family members Meth Enzymol Methods in Enzymology 200 38 62 doi 10 1016 0076 6879 91 00126 H ISBN 9780121821012 PMID 1956325 Modi V Dunbrack RL 2019 12 24 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 Knighton DR Zheng JH Ten Eyck LF Ashford VA Xuong NH Taylor SS Sowadski JM July 1991 Crystal structure of the catalytic subunit of cyclic adenosine monophosphate dependent protein kinase Science 253 5018 407 14 Bibcode 1991Sci 253 407K doi 10 1126 science 1862342 PMID 1862342 Higashiyama S Iwabuki H Morimoto C Hieda M Inoue H Matsushita N Membrane anchored growth factors the epidermal growth factor family beyond receptor ligands Cancer Sci 2008 Feb 99 2 214 20 Review PMID 18271917 Carpenter G The EGF receptor a nexus for trafficking and signaling Bioessays 2000 Aug 22 8 697 707 Review PMID 10918300External links Edit Biology portalHuman and mouse protein kinases in UniProt classification and index Kinase Com Genomics evolution and large scale analysis of protein kinases non commercial KinMutBase A registry of disease causing mutations in protein kinase domains KLIFS Kinase Ligand Interaction Fingerprints and Structures Database analysis of kinase structures and kinase inhibitor interactions KinCore the Kinase Conformation Resource A web resource for protein kinase sequence structure and phylogeny Kinomer A multilevel HMM library for the classification and functional annotation of eukaryotic protein kinases Retrieved from https en wikipedia org w index php title Protein kinase amp oldid 1124080401, wikipedia, wiki, book, books, library,

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