Pseudokinase

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Pseudokinases are catalytically-deficient pseudoenzyme [1] variants of protein kinases that are represented in all kinomes across the kingdoms of life. Pseudokinases have both physiological (signal transduction) and pathophysiological functions. [2] [3] [4] [5] [6] [7] [8]

Contents

History

The phrase pseudokinase was first coined in 2002. [9] They were subsequently sub-classified into different 'classes'. [10] [8] [11] [12] [13] Several pseudokinase-containing families are found in the human kinome, including the Tribbles pseudokinases, which are at the interface between kinase and ubiquitin E3 ligase signalling. [14] [15] [16]

The human pseudokinases (and their pseudophosphatase cousins) are implicated in a wide variety of diseases, [17] [18] which has made them potential drug targets and antitargets). [19] [20] [21] [22] Pseudokinases are made up of an evolutionary mixture of eukaryotic protein kinase (ePK) and non ePK-related pseudoenzyme proteins (e.g., FAM20A, which binds ATP [23] and is pseudokinase due to a conserved glutamate to glutamine swap in the alpha-C helix. [24] FAM20A is implicated in periodontal disease, and serves to control the catalytic activity of FAM20C, an important physiological casein kinase that controls phosphorylation of proteins in the Golgi apparatus that are destined for secretion, [25] such as the milk protein casein.

A comprehensive evolutionary analysis confirms that pseudokinases group into multiple subfamilies, and these are found in the annotated kinome of organisms across the kingdoms of life, including prokaryotes, archaea and all eukaryotic lineages with an annotated proteome; this data is searchable in ProKino (http://vulcan.cs.uga.edu/prokino/about/browser). [26]

See also

Related Research Articles

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Enzymes are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrates, and the enzyme converts the substrates into different molecules known as products. Almost all metabolic processes in the cell need enzyme catalysis in order to occur at rates fast enough to sustain life. Metabolic pathways depend upon enzymes to catalyze individual steps. The study of enzymes is called enzymology and the field of pseudoenzyme analysis recognizes that during evolution, some enzymes have lost the ability to carry out biological catalysis, which is often reflected in their amino acid sequences and unusual 'pseudocatalytic' properties.

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">Signal transduction</span> Cascade of intracellular and molecular events for transmission/amplification of signals

Signal transduction is the process by which a chemical or physical signal is transmitted through a cell as a series of molecular events. Proteins responsible for detecting stimuli are generally termed receptors, although in some cases the term sensor is used. The changes elicited by ligand binding in a receptor give rise to a biochemical cascade, which is a chain of biochemical events known as a signaling pathway.

<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.

<span class="mw-page-title-main">Phosphorylation</span> Chemical process of introducing a phosphate

In biochemistry, phosphorylation is the attachment of a phosphate group to a molecule or an ion. This process and its inverse, dephosphorylation, are common in biology. Protein phosphorylation often activates many enzymes.

<span class="mw-page-title-main">Protein kinase A</span> Family of enzymes

In cell biology, protein kinase A (PKA) is a family of serine-threonine kinase 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.

<span class="mw-page-title-main">Phosphatase</span> Enzyme which catalyzes the removal of a phosphate group from a molecule

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A mitogen-activated protein kinase is a type of serine/threonine-specific protein kinases involved in directing cellular responses to a diverse array of stimuli, such as mitogens, osmotic stress, heat shock and proinflammatory cytokines. They regulate cell functions including proliferation, gene expression, differentiation, mitosis, cell survival, and apoptosis.

Phosphatidic acids are anionic phospholipids important to cell signaling and direct activation of lipid-gated ion channels. Hydrolysis of phosphatidic acid gives rise to one molecule each of glycerol and phosphoric acid and two molecules of fatty acids. They constitute about 0.25% of phospholipids in the bilayer.

CAMK, also written as CaMK or CCaMK, is an abbreviation for the Ca2+/calmodulin-dependent protein kinase class of enzymes. CAMKs are activated by increases in the concentration of intracellular calcium ions (Ca2+) and calmodulin. When activated, the enzymes transfer phosphates from ATP to defined serine or threonine residues in other proteins, so they are serine/threonine-specific protein kinases. Activated CAMK is involved in the phosphorylation of transcription factors and therefore, in the regulation of expression of responding genes. CAMK also works to regulate the cell life cycle (i.e. programmed cell death), rearrangement of the cell's cytoskeletal network, and mechanisms involved in the learning and memory of an organism.

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

A serine/threonine protein kinase 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).

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.

<span class="mw-page-title-main">STK11</span> Protein-coding gene in the species Homo sapiens

Serine/threonine kinase 11 (STK11) also known as liver kinase B1 (LKB1) or renal carcinoma antigen NY-REN-19 is a protein kinase that in humans is encoded by the STK11 gene.

<span class="mw-page-title-main">Histidine kinase</span> Family of enzymes important in cell signaling

Histidine kinases (HK) are multifunctional, and in non-animal kingdoms, typically transmembrane, proteins of the transferase class of enzymes that play a role in signal transduction across the cellular membrane. The vast majority of HKs are homodimers that exhibit autokinase, phosphotransfer, and phosphatase activity. HKs can act as cellular receptors for signaling molecules in a way analogous to tyrosine kinase receptors (RTK). Multifunctional receptor molecules such as HKs and RTKs typically have portions on the outside of the cell that bind to hormone- or growth factor-like molecules, portions that span the cell membrane, and portions within the cell that contain the enzymatic activity. In addition to kinase activity, the intracellular domains typically have regions that bind to a secondary effector molecule or complex of molecules that further propagate signal transduction within the cell. Distinct from other classes of protein kinases, HKs are usually parts of a two-component signal transduction mechanisms in which HK transfers a phosphate group from ATP to a histidine residue within the kinase, and then to an aspartate residue on the receiver domain of a response regulator protein. More recently, the widespread existence of protein histidine phosphorylation distinct from that of two-component histidine kinases has been recognised in human cells. In marked contrast to Ser, Thr and Tyr phosphorylation, the analysis of phosphorylated Histidine using standard biochemical and mass spectrometric approaches is much more challenging, and special procedures and separation techniques are required for their preservation alongside classical Ser, Thr and Tyr phosphorylation on proteins isolated from human cells.

<span class="mw-page-title-main">TRIB3</span> Protein-coding gene in the species Homo sapiens

Tribbles homolog 3 is a protein that in humans is encoded by the TRIB3 gene.

<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.

<span class="mw-page-title-main">TRIB1</span> Protein-coding gene in the species Homo sapiens

Tribbles homolog 1 is a protein kinase that in humans is encoded by the TRIB1 gene. Orthologs of this protein pseudokinase (pseudoenzyme) can be found almost ubiquitously throughout the animal kingdom. It exerts its biological functions through binding to signalling proteins of the MAPKK level of the MAPK pathway, therefore eliciting a regulatory role in the function of this pathway which mediates proliferation, apoptosis and differentiation in cells. Tribbles-1 is encoded by the trib1 gene, which in humans can be found on chromosome 8 at position 24.13 on the longest arm (q). Recent crystal structures show that Tribbles 1 has an unusual 3D structure, containing a 'broken' C-helix region, a binding site for ubiquitinated substrates such as C/EBPalpha and a key regulatory C-tail region. Like TRIB2 and TRIB3, TRIB1 has recently been considered as a potential allosteric drug target.

<span class="mw-page-title-main">TRIB2</span> Protein-coding gene in the species Homo sapiens

Tribbles homolog 2 is an atypical protein kinase that is encoded in human by the TRIB2 gene. TRIB2 is a pseudokinase member of the (pseudoenzyme) class of signaling/scaffold proteins, possessing very low vestigial catalytic output in vitro and critical scaffolding signaling functions in cells. It is known to signal to canonical MAPK and AKT pathways and to regulate the ubiquitination of substrates with important functions in cell proliferation that control the cell ccyle. It has also been associated with various diseases, especially in human and murine blood and solid tumor models. Like TRIB1 and TRIB3, TRIB2 has recently been considered as a potential allosteric drug target, and its three dimensional structure has been solved with the aid of stabilizing nanobodies corroborating the potential for new approaches for drug targeting outside the highly degraded ATP site and is a putative regulator of cancer-associated signalling and survival through AKT pSer473 modulation. Recent work has established a convincing link between targetable overexpression of TRIB2 and prostate cancer drug responses

Pseudoenzymes are variants of enzymes that are catalytically-deficient, meaning that they perform little or no enzyme catalysis. They are believed to be represented in all major enzyme families in the kingdoms of life, where they have important signaling and metabolic functions, many of which are only now coming to light. Pseudoenzymes are becoming increasingly important to analyse, especially as the bioinformatic analysis of genomes reveals their ubiquity. Their important regulatory and sometimes disease-associated functions in metabolic and signalling pathways are also shedding new light on the non-catalytic functions of active enzymes, of moonlighting proteins, the re-purposing of proteins in distinct cellular roles. They are also suggesting new ways to target and interpret cellular signalling mechanisms using small molecules and drugs. The most intensively analyzed, and certainly the best understood pseudoenzymes in terms of cellular signalling functions are probably the pseudokinases, the pseudoproteases and the pseudophosphatases. Recently, the pseudo-deubiquitylases have also begun to gain prominence.

The phosphatome of an organism is the set of phosphatase genes in its genome. Phosphatases are enzymes that catalyze the removal of phosphate from biomolecules. Over half of all cellular proteins are modified by phosphorylation which typically controls their functions. Protein phosphorylation is controlled by the opposing actions of protein phosphatases and protein kinases. Most phosphorylation sites are not linked to a specific phosphatase, so the phosphatome approach allows a global analysis of dephosphorylation, screening to find the phosphatase responsible for a given reaction, and comparative studies between different phosphatases, similar to how protein kinase research has been impacted by the kinome approach.

References

  1. ↑ Murphy JM, Farhan H, Eyers PA (April 2017). "Bio-Zombie: the rise of pseudoenzymes in biology". Biochemical Society Transactions. 45 (2): 537–544. doi:10.1042/BST20160400. PMID   28408493.
  2. ↑ Jacobsen AV, Murphy JM (June 2017). "The secret life of kinases: insights into non-catalytic signalling functions from pseudokinases". Biochemical Society Transactions. 45 (3): 665–681. doi: 10.1042/BST20160331 . PMID   28620028.
  3. ↑ Murphy JM, Zhang Q, Young SN, Reese ML, Bailey FP, Eyers PA, Ungureanu D, Hammaren H, Silvennoinen O, Varghese LN, Chen K, Tripaydonis A, Jura N, Fukuda K, Qin J, Nimchuk Z, Mudgett MB, Elowe S, Gee CL, Liu L, Daly RJ, Manning G, Babon JJ, Lucet IS (January 2014). "A robust methodology to subclassify pseudokinases based on their nucleotide-binding properties". The Biochemical Journal. 457 (2): 323–34. doi:10.1042/BJ20131174. PMC   5679212 . PMID   24107129.
  4. ↑ Kannan N, Taylor SS (April 2008). "Rethinking pseudokinases". Cell. 133 (2): 204–5. doi:10.1016/j.cell.2008.04.005. PMC   6226312 . PMID   18423189.
  5. ↑ Mukherjee K, Sharma M, Urlaub H, Bourenkov GP, Jahn R, Südhof TC, Wahl MC (April 2008). "CASK Functions as a Mg2+-independent neurexin kinase". Cell. 133 (2): 328–39. doi:10.1016/j.cell.2008.02.036. PMC   3640377 . PMID   18423203.
  6. ↑ Bailey FP, Byrne DP, Oruganty K, Eyers CE, Novotny CJ, Shokat KM, Kannan N, Eyers PA (April 2015). "The Tribbles 2 (TRB2) pseudokinase binds to ATP and autophosphorylates in a metal-independent manner". The Biochemical Journal. 467 (1): 47–62. doi:10.1042/BJ20141441. PMC   4844368 . PMID   25583260.
  7. ↑ Shi F, Telesco SE, Liu Y, Radhakrishnan R, Lemmon MA (April 2010). "ErbB3/HER3 intracellular domain is competent to bind ATP and catalyze autophosphorylation". Proceedings of the National Academy of Sciences of the United States of America. 107 (17): 7692–7. Bibcode:2010PNAS..107.7692S. doi: 10.1073/pnas.1002753107 . PMC   2867849 . PMID   20351256.
  8. 1 2 Zeqiraj E, Filippi BM, Deak M, Alessi DR, van Aalten DM (December 2009). "Structure of the LKB1-STRAD-MO25 complex reveals an allosteric mechanism of kinase activation". Science. 326 (5960): 1707–11. Bibcode:2009Sci...326.1707Z. doi:10.1126/science.1178377. PMC   3518268 . PMID   19892943.
  9. ↑ Manning G, Whyte DB, Martinez R, Hunter T, Sudarsanam S (December 2002). "The protein kinase complement of the human genome". Science. 298 (5600): 1912–34. Bibcode:2002Sci...298.1912M. doi:10.1126/science.1075762. PMID   12471243. S2CID   26554314.
  10. ↑ Boudeau J, Miranda-Saavedra D, Barton GJ, Alessi DR (September 2006). "Emerging roles of pseudokinases". Trends in Cell Biology. 16 (9): 443–52. doi:10.1016/j.tcb.2006.07.003. PMID   16879967.
  11. ↑ Zeqiraj E, van Aalten DM (December 2010). "Pseudokinases-remnants of evolution or key allosteric regulators?". Current Opinion in Structural Biology. 20 (6): 772–81. doi:10.1016/j.sbi.2010.10.001. PMC   3014569 . PMID   21074407.
  12. ↑ Scheeff ED, Eswaran J, Bunkoczi G, Knapp S, Manning G (January 2009). "Structure of the pseudokinase VRK3 reveals a degraded catalytic site, a highly conserved kinase fold, and a putative regulatory binding site". Structure. 17 (1): 128–38. doi:10.1016/j.str.2008.10.018. PMC   2639636 . PMID   19141289.
  13. ↑ Eyers PA, Murphy JM (August 2013). "Dawn of the dead: protein pseudokinases signal new adventures in cell biology". Biochemical Society Transactions. 41 (4): 969–74. doi:10.1042/BST20130115. PMID   23863165.
  14. ↑ Eyers PA, Keeshan K, Kannan N (April 2017). "Tribbles in the 21st Century: The Evolving Roles of Tribbles Pseudokinases in Biology and Disease". Trends in Cell Biology. 27 (4): 284–298. doi:10.1016/j.tcb.2016.11.002. PMC   5382568 . PMID   27908682.
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  16. ↑ Jamieson SA, Ruan Z, Burgess AE, Curry JR, McMillan HD, Brewster JL, Dunbier AK, Axtman AD, Kannan N, Mace PD (September 2018). "Substrate binding allosterically relieves autoinhibition of the pseudokinase TRIB1". Science Signaling. 11 (549): eaau0597. doi:10.1126/scisignal.aau0597. PMC   6553639 . PMID   30254053.
  17. ↑ Reiterer V, Eyers PA, Farhan H (September 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.
  18. ↑ Chen MJ, Dixon JE, Manning G (April 2017). "Genomics and evolution of protein phosphatases". Science Signaling. 10 (474): eaag1796. doi:10.1126/scisignal.aag1796. PMID   28400531. S2CID   41041971.
  19. ↑ Byrne DP, Foulkes DM, Eyers PA (January 2017). "Pseudokinases: update on their functions and evaluation as new drug targets". Future Medicinal Chemistry . 9 (2): 245–265. doi: 10.4155/fmc-2016-0207 . PMID   28097887.
  20. ↑ Bailey FP, Byrne DP, McSkimming D, Kannan N, Eyers PA (January 2015). "Going for broke: targeting the human cancer pseudokinome". The Biochemical Journal. 465 (2): 195–211. doi:10.1042/BJ20141060. PMID   25559089.
  21. ↑ Cowan-Jacob SW, Jahnke W, Knapp S (April 2014). "Novel approaches for targeting kinases: allosteric inhibition, allosteric activation and pseudokinases". Future Medicinal Chemistry . 6 (5): 541–61. doi:10.4155/fmc.13.216. PMID   24649957.
  22. ↑ Foulkes DM, Byrne DP, Bailey FP, Eyers PA (October 2015). "Tribbles pseudokinases: novel targets for chemical biology and drug discovery?". Biochemical Society Transactions. 43 (5): 1095–103. doi:10.1042/BST20150109. PMID   26517930.
  23. ↑ Cui J, Zhu Q, Zhang H, Cianfrocco MA, Leschziner AE, Dixon JE, Xiao J (April 2017). "Structure of Fam20A reveals a pseudokinase featuring a unique disulfide pattern and inverted ATP-binding". eLife. 6. doi: 10.7554/eLife.23990 . PMC   5413348 . PMID   28432788.
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