Pseudoenzyme

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Pseudoenzymes are variants of enzymes that are catalytically-deficient (usually inactive), meaning that they perform little or no enzyme catalysis. [1] 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. [2] 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, [3] [4] the re-purposing of proteins in distinct cellular roles (Protein moonlighting). They are also suggesting new ways to target and interpret cellular signalling mechanisms using small molecules and drugs. [5] 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. [6] [7]

Contents

Structures and roles

The difference between enzymatically active and inactive homologues has been noted (and in some cases, understood when comparing catalytically active and inactive proteins residing in recognisable families) for some time at the sequence level, [8] owing to the absence of key catalytic residues. Some pseudoenzymes have also been referred to as 'prozymes' when they were analysed in protozoan parasites. [9] The best studied pseudoenzymes reside amongst various key signalling superfamilies of enzymes, such as the proteases, [10] the protein kinases, [11] [12] [13] [14] [15] [16] [17] protein phosphatases [18] [19] and ubiquitin modifying enzymes. [20] [21] The role of pseudoenzymes as "pseudo scaffolds" has also been recognised [22] and pseudoenzymes are now beginning to be more thoroughly studied in terms of their biology and function, in large part because they are also interesting potential targets (or anti-targets) for drug design in the context of intracellular cellular signalling complexes. [23] [24]

Examples classes

ClassFunctionExamples [25]
Pseudokinase Allosteric regulation of conventional protein kinaseSTRADα regulates activity of the conventional protein kinase, LKB1

JAK1-3 and TYK2 C-terminal tyrosine kinase domains are regulated by their adjacent pseudokinase domain KSR1/2 regulates activation of the conventional protein kinase, Raf

Allosteric regulation of other enzymesVRK3 regulates activity of the phosphatase, VHR
Pseudo-Histidine kinaseProtein interaction domainCaulobacter DivL binds the phosphorylated response regulator, DivK, allowing DivL to negatively regulate the asymmetric cell division regulatory kinase, CckA
PseudophosphataseOcclusion of conventional phosphatase access to substrateEGG-4/EGG-5 binds to the phosphorylated activation loop of the kinase, MBK-2

STYX competes with DUSP4 for binding to ERK1/2

Allosteric regulation of conventional phosphatasesMTMR13 binds and promotes lipid phosphatase activity of MTMR2
Regulation of protein localisation in a cellSTYX acts as a nuclear anchor for ERK1/2
Regulation of signalling complex assemblySTYX binds the F-box protein, FBXW7, to inhibit its recruitment to the SCF Ubiquitin ligase complex
Pseudoprotease Allosteric regulator of conventional proteasecFLIP binds and inhibits the cysteine protease, Caspase-8, to block extrinsic apoptosis
Regulation of protein localisation in a cellMammalian iRhom proteins bind and regulate trafficking single pass transmembrane proteins to plasma membrane or ER-associated degradation pathway
Pseudodeubiquitinase (pseudoDUB)Allosteric regulator of conventional DUBKIAA0157 is crucial to assembly of a higher order heterotetramer with DUB, BRCC36, and DUB activity
Pseudoligase (pseudo-Ubiquitin E2)Allosteric regulator of conventional E2 ligaseMms2 is a ubiquitin E2 variant (UEV) that binds active E2, Ubc13, to direct K63 ubiquitin linkages
Regulation of protein localisation in a cellTsg101 is a component of the ESCRT-I trafficking complex, and plays a key role in HIV-1 Gag binding and HIV budding
Pseudoligase (pseudo-Ubiquitin E3)Possible allosteric regulator of conventional RBR family E3 ligaseBRcat regulates interdomain architecture in RBR family E3 Ubiquitin ligases, such as Parkin and Ariadne-1/2
PseudonucleaseAllosteric regulator of conventional nucleaseCPSF-100 is a component of the pre-mRNA 3´ end processing complex containing the active counterpart, CPSF-73
PseudoATPaseAllosteric regulator of conventional ATPaseEccC comprises two pseudoATPase domains that regulate the N-terminal conventional ATPase domain
PseudoGTPaseAllosteric regulator of conventional GTPaseGTP-bound Rnd1 or Rnd3/RhoE bind p190RhoGAP to regulate the catalytic activity of the conventional GTPase, RhoA
Scaffold for assembly of signalling complexesMiD51, which is catalytically dead but binds GDP or ADP, is part of a complex that recruits Drp1 to mediate mitochondrial fission. CENP-M cannot bind GTP or switch conformations, but is essential for nucleating the CENP-I, CENP-H, CENP-K small GTPase complex to regulate kinetochore assembly
Regulation of protein localisation in a cellYeast light intermediate domain (LIC) is a pseudoGTPase, devoid of nucleotide binding, which binds the dynein motor to cargo. Human LIC binds GDP in preference to GTP, suggesting nucleotide binding could confer stability rather than underlying a switch mechanism.
PseudochitinaseSubstrate recruitment or sequestrationYKL-39 binds, but does not process, chitooligosaccharides via 5 binding subsites
PseudosialidaseScaffold for assembly of signalling complexesCyRPA nucleates assembly of the P. falciparum PfRh5/PfRipr complex that binds the erythrocyte receptor, basigin, and mediates host cell invasion
PseudolyaseAllosteric activation of conventional enzyme counterpartProzyme heterodimerisation with S-adenosylmethionine decarboxylase (AdoMetDC) activates catalytic activity 1000-fold
PseudotransferaseAllosteric activation of cellular enzyme counterpartViral GAT recruits cellular PFAS to deaminate RIG-I and counter host antiviral defence. T. brucei deoxyhypusine synthase (TbDHS) dead paralog, DHSp, binds to and activates DHSc >1000-fold.
Pseudo-histone acetyl transferase (pseudoHAT)Possible scaffold for assembly of signalling complexesHuman O-GlcNAcase (OGA) lacks catalytic residues and acetyl CoA binding, unlike bacterial counterpart
Pseudo-phospholipasePossible scaffold for assembly of signalling complexesFAM83 family proteins presumed to have acquired new functions in preference to ancestral phospholipase D catalytic activity
Allosteric inactivation of conventional enzyme counterpartViper phospholipase A2 inhibitor structurally resembles the human cellular protein it targets, phospholipase A2.
Pseudo-oxidoreductaseAllosteric inactivation of conventional enzyme counterpartALDH2*2 thwarts assembly of the active counterpart, ALDH2*1, into a tetramer.
Pseudo-dismutaseAllosteric activation of conventional enzyme counterpartCopper chaperone for superoxide dismutase (CCS) binds and activates catalysis by its enzyme counterpart, SOD1
Pseudo-dihydroorotaseRegulating folding or complex assembly of conventional enzymePseudomonas pDHO is required for either folding of the aspartate transcarbamoylase catalytic subunit, or its assembly into an active oligomer
Pseudo-RNaseFacilitating complex assembly/stability and promoting association of catalytic paralogKREPB4 may act as a pseudoenzyme to form the noncatalytic half of an RNase III heterodimer with the editing endonuclease(s) [26]

See also

Related Research Articles

<span class="mw-page-title-main">Enzyme</span> Large biological molecule that acts as a catalyst

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">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">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

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 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.

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">Catalytic triad</span> Set of three coordinated amino acids

A catalytic triad is a set of three coordinated amino acids that can be found in the active site of some enzymes. Catalytic triads are most commonly found in hydrolase and transferase enzymes. An acid-base-nucleophile triad is a common motif for generating a nucleophilic residue for covalent catalysis. The residues form a charge-relay network to polarise and activate the nucleophile, which attacks the substrate, forming a covalent intermediate which is then hydrolysed to release the product and regenerate free enzyme. The nucleophile is most commonly a serine or cysteine amino acid, but occasionally threonine or even selenocysteine. The 3D structure of the enzyme brings together the triad residues in a precise orientation, even though they may be far apart in the sequence.

<span class="mw-page-title-main">Protein tyrosine phosphatase</span> Class of enzymes

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:

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">DUSP1</span> Protein-coding gene in the species Homo sapiens

Dual specificity protein phosphatase 1 is an enzyme that in humans is encoded by the DUSP1 gene.

<span class="mw-page-title-main">PPP2R5A</span> Enzyme found in humans

Serine/threonine-protein phosphatase 2A 56 kDa regulatory subunit alpha isoform is an enzyme that in humans is encoded by the PPP2R5A gene.

<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">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">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

<span class="mw-page-title-main">Protein phosphatase 1</span>

Protein phosphatase 1 (PP1) belongs to a certain class of phosphatases known as protein serine/threonine phosphatases. This type of phosphatase includes metal-dependent protein phosphatases (PPMs) and aspartate-based phosphatases. PP1 has been found to be important in the control of glycogen metabolism, muscle contraction, cell progression, neuronal activities, splicing of RNA, mitosis, cell division, apoptosis, protein synthesis, and regulation of membrane receptors and channels.

<span class="mw-page-title-main">MAPK phosphatase</span>

MAPK phosphatases (MKPs) are the largest class of phosphatases involved in down-regulating Mitogen-activated protein kinases (MAPK) signaling. MAPK signalling pathways regulate multiple features of development and homeostasis. This can involve gene regulation, cell proliferation, programmed cell death and stress responses. MAPK phosphatases are therefore important regulator components of these pathways.

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.

Pseudokinases are catalytically-deficient pseudoenzyme variants of protein kinases that are represented in all kinomes across the kingdoms of life. Pseudokinases have both physiological and pathophysiological functions.

References

  1. ↑ Ribeiro AJ, Das S, Dawson N, Zaru R, Orchard S, Thornton JM, Orengo C, Zeqiraj E, Murphy JM, Eyers PA (Aug 2019). "Emerging concepts in pseudoenzyme classification, evolution, and signaling". Science Signaling. 12 (594): eaat9797. doi:10.1126/scisignal.aat9797. PMID   31409758.
  2. ↑ Kwon A, Scott S, Taujale R, Yeung W, Kochut KJ, Eyers PA, Kannan N (April 2019). "Tracing the origin and evolution of pseudokinases across the tree of life". Science Signaling. 12 (578): eaav3810. doi:10.1126/scisignal.aav3810. PMC   6997932 . PMID   31015289.
  3. ↑ Jeffery CJ (Feb 2019). "The demise of catalysis, but new functions arise: pseudoenzymes as the phoenixes of the protein world". Biochemical Society Transactions. 47 (1): 371–379. doi:10.1042/BST20180473. PMID   30710059. S2CID   73437705.
  4. ↑ Jeffery CJ (Dec 2019). "Multitalented actors inside and outside the cell: recent discoveries add to the number of moonlighting proteins". Biochemical Society Transactions. 47 (6): 1941–1948. doi:10.1042/BST20190798. PMID   31803903. S2CID   208643133.
  5. ↑ Eyers PA, Murphy JM (November 2016). "The evolving world of pseudoenzymes: proteins, prejudice and zombies". BMC Biology. 14 (1): 98. doi: 10.1186/s12915-016-0322-x . PMC   5106787 . PMID   27835992.
  6. ↑ Walden M, Masandi SK, Pawlowski K, Zeqiraj E (Feb 2018). "Pseudo-DUBs as allosteric activators and molecular scaffolds of protein complexes" (PDF). Biochem Soc Trans. 46 (2): 453–466. doi:10.1042/BST20160268. PMID   29472364. S2CID   3477709.
  7. ↑ Walden M, Tian L, Ross RL, Sykora UM, Byrne DP, Hesketh EL, Masandi SK, Cassel J, George R, Ault JR, El Oualid F, Pawłowski K, Salvino JM, Eyers PA, Ranson NA, Del Galdo F, Greenberg RA, Zeqiraj E (May 2019). "Metabolic control of BRISC–SHMT2 assembly regulates immune signalling" (PDF). Nature. 570 (7760): 194–199. Bibcode:2019Natur.570..194W. doi:10.1038/s41586-019-1232-1. PMC   6914362 . PMID   31142841.
  8. ↑ Todd AE, Orengo CA, Thornton JM (October 2002). "Sequence and structural differences between enzyme and nonenzyme homologs". Structure. 10 (10): 1435–51. doi: 10.1016/s0969-2126(02)00861-4 . PMID   12377129.
  9. ↑ Willert EK, Fitzpatrick R, Phillips MA (May 2007). "Allosteric regulation of an essential trypanosome polyamine biosynthetic enzyme by a catalytically dead homolog". Proceedings of the National Academy of Sciences of the United States of America. 104 (20): 8275–80. Bibcode:2007PNAS..104.8275W. doi: 10.1073/pnas.0701111104 . PMC   1895940 . PMID   17485680.
  10. ↑ Adrain C, Freeman M (July 2012). "New lives for old: evolution of pseudoenzyme function illustrated by iRhoms". Nature Reviews. Molecular Cell Biology. 13 (8): 489–98. doi:10.1038/nrm3392. PMID   22781900. S2CID   806199.
  11. ↑ Kwon A, Scott S, Taujale R, Yeung W, Kochut KJ, Eyers PA, Kannan N (April 2019). "Tracing the origin and evolution of pseudokinases across the tree of life". Science Signaling. 12 (578): eaav3810. doi:10.1126/scisignal.aav3810. PMC   6997932 . PMID   31015289.
  12. ↑ 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.
  13. ↑ 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.
  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.
  15. ↑ 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.
  16. ↑ Murphy JM, Czabotar PE, Hildebrand JM, Lucet IS, Zhang JG, Alvarez-Diaz S, Lewis R, Lalaoui N, Metcalf D, Webb AI, Young SN, Varghese LN, Tannahill GM, Hatchell EC, Majewski IJ, Okamoto T, Dobson RC, Hilton DJ, Babon JJ, Nicola NA, Strasser A, Silke J, Alexander WS (September 2013). "The pseudokinase MLKL mediates necroptosis via a molecular switch mechanism". Immunity. 39 (3): 443–53. doi: 10.1016/j.immuni.2013.06.018 . PMID   24012422.
  17. ↑ Wishart MJ, Dixon JE (August 1998). "Gathering STYX: phosphatase-like form predicts functions for unique protein-interaction domains". Trends in Biochemical Sciences. 23 (8): 301–6. doi:10.1016/s0968-0004(98)01241-9. PMID   9757831.
  18. ↑ 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.
  19. ↑ 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.
  20. ↑ Zeqiraj E, Tian L, Piggott CA, Pillon MC, Duffy NM, Ceccarelli DF, Keszei AF, Lorenzen K, Kurinov I, Orlicky S, Gish GD, Heck AJ, Guarné A, Greenberg RA, Sicheri F (September 2015). "Higher-Order Assembly of BRCC36-KIAA0157 Is Required for DUB Activity and Biological Function". Molecular Cell. 59 (6): 970–83. doi:10.1016/j.molcel.2015.07.028. PMC   4579573 . PMID   26344097.
  21. ↑ Strickson S, Emmerich CH, Goh ET, Zhang J, Kelsall IR, Macartney T, Hastie CJ, Knebel A, Peggie M, Marchesi F, Arthur JS, Cohen P (April 2017). "Roles of the TRAF6 and Pellino E3 ligases in MyD88 and RANKL signaling". Proceedings of the National Academy of Sciences of the United States of America. 114 (17): E3481–E3489. Bibcode:2017PNAS..114E3481S. doi: 10.1073/pnas.1702367114 . PMC   5410814 . PMID   28404732.
  22. ↑ Aggarwal-Howarth S, Scott JD (April 2017). "Pseudoscaffolds and anchoring proteins: the difference is in the details". Biochemical Society Transactions. 45 (2): 371–379. doi:10.1042/bst20160329. PMC   5497583 . PMID   28408477.
  23. ↑ 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.
  24. ↑ 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.
  25. ↑ 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.
  26. ↑ McDermott SM, Stuart K (November 2017). "The essential functions of KREPB4 are developmentally distinct and required for endonuclease association with editosomes". RNA. 23 (11): 1672–1684. doi:10.1261/rna.062786.117. PMC   5648035 . PMID   28802260.
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