Pseudoenzyme

Pseudoenzymes are catalytically-deficient (usually inactive) variants of enzymes (usually proteins) that are believed to be represented in all major enzyme families in the kingdoms of life. 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, and are suggesting new ways to target and interpret cellular signalling mechanisms using small molecules and drugs.[1] 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.

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,[2] and some pseudoenzymes have also been referred to as 'prozymes' when they were analysed in protozoan parasites.[3] The best studied pseudoenzymes reside amongst various key signalling superfamilies of enzymes, such as the proteases,[4] the protein kinases,[5][6][7][8][9][10] protein phosphatases [11][12] and ubiquitin modifying enzymes.[13][14] The role of pseudoenzymes as "pseudo scaffolds" has also been recognised [15] 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.[16][17]

Examples of different pseudoenzyme classes, see reference [18] for specific citations

Class Function Examples
Pseudokinase Allosteric regulation of conventional protein kinase STRADα 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 enzymes VRK3 regulates activity of the phosphatase, VHR
Pseudo-Histidine kinase Protein interaction domain Caulobacter DivL binds the phosphorylated response regulator, DivK, allowing DivL to negatively regulate the asymmetric cell division regulatory kinase, CckA
Pseudophosphatase Occlusion of conventional phosphatase access to substrate EGG-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 phosphatases MTMR13 binds and promotes lipid phosphatase activity of MTMR2
Regulation of protein localisation in a cell STYX acts as a nuclear anchor for ERK1/2
Regulation of signalling complex assembly STYX binds the F-box protein, FBXW7, to inhibit its recruitment to the SCF Ubiquitin ligase complex
Pseudoprotease Allosteric regulator of conventional protease cFLIP binds and inhibits the cysteine protease, Caspase-8, to block extrinsic apoptosis
Regulation of protein localisation in a cell Mammalian iRhom proteins bind and regulate trafficking single pass transmembrane proteins to plasma membrane or ER-associated degradation pathway
Pseudodeubiquitinase (pseudoDUB) Allosteric regulator of conventional DUB KIAA0157 is crucial to assembly of a higher order heterotetramer with DUB, BRCC36, and DUB activity
Pseudoligase (pseudo-Ubiquitin E2) Allosteric regulator of conventional E2 ligase Mms2 is a ubiquitin E2 variant (UEV) that binds active E2, Ubc13, to direct K63 ubiquitin linkages
Regulation of protein localisation in a cell Tsg101 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 ligase BRcat regulates interdomain architechure in RBR family E3 Ubiquitin ligases, such as Parkin and Ariadne-1/2
Pseudonuclease Allosteric regulator of conventional nuclease CPSF-100 is a component of the pre-mRNA 3´ end processing complex containing the active counterpart, CPSF-73
PseudoATPase Allosteric regulator of conventional ATPase EccC comprises two pseudoATPase domains that regulate the N-terminal conventional ATPase domain
PseudoGTPase Allosteric regulator of conventional GTPase GTP-bound Rnd1 or Rnd3/RhoE bind p190RhoGAP to regulate the catalytic activity of the conventional GTPase, RhoA
Scaffold for assembly of signalling complexes MiD51, 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 cell Yeast 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.
Pseudochitinase Substrate recruitment or sequestration YKL-39 binds, but does not process, chitooligosaccharides via 5 binding subsites
Pseudosialidase Scaffold for assembly of signalling complexes CyRPA nucleates assembly of the P. falciparum PfRh5/PfRipr complex that binds the erythrocyte receptor, basigin, and mediates host cell invasion
Pseudolyase Allosteric activation of conventional enzyme counterpart Prozyme heterodimerisation with S-adenosylmethionine decarboxylase (AdoMetDC) activates catalytic activity 1000-fold
Pseudotransferase Allosteric activation of cellular enzyme counterpart Viral 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 complexes Human O-GlcNAcase (OGA) lacks catalytic residues and acetyl CoA binding, unlike bacterial counterpart
Pseudo-phospholipase Possible scaffold for assembly of signalling complexes FAM83 family proteins presumed to have acquired new functions in preference to ancestral phospholipase D catalytic activity
Allosteric inactivation of conventional enzyme counterpart Viper phospholipase A2 inhibitor structurally resembles the human cellular protein it targets, phospholipase A2.
Pseudo-oxidoreductase Allosteric inactivation of conventional enzyme counterpart ALDH2*2 thwarts assembly of the active counterpart, ALDH2*1, into a tetramer.
Pseudo-dismutase Allosteric activation of conventional enzyme counterpart Copper chaperone for superoxide dismutase (CCS) binds and activates catalysis by its enzyme counterpart, SOD1
Pseudo-dihydroorotase Regulating folding or complex assembly of conventional enzyme Pseudomonas pDHO is required for either folding of the aspartate transcarbamoylase catalytic subunit, or its assembly into an active oligomer

Conferences and collaboration

The world's first pseudoenyzme meeting took place in September 2016 in Liverpool, UK.[19] Sponsored by the Biochemical Society,[20] it brought together a highly diverse group of scientists to discuss, celebrate and expand the fledgling pseudoenzyme field.[21] The second international pseudoenzyme meeting will be an official workshop sponsored by EMBO, and will take place between 16th and 19th May 2018 in Sardinia, Italy [22]

See also

References

  1. ↑ Eyers, PA; Murphy, JM (2016). "The evolving world of pseudoenzymes: proteins, prejudice and zombies". BMC Biol. 14: 98. doi:10.1186/s12915-016-0322-x.
  2. ↑ Todd, AE; Orengo, CA; Thornton, JM (2002). "Sequence and structural differences between enzyme and nonenzyme homologs". Structure. 10: 1435–51. doi:10.1016/s0969-2126(02)00861-4.
  3. ↑ Willert, E.K.; Phillips, M.A. (2007). "Allosteric regulation of an essential trypanosome polyamine biosynthetic enzyme by a catalytically dead homolog". Proc. Natl. Acad. Sci. USA. 104: 8275–8280. doi:10.1073/pnas.0701111104.
  4. ↑ Adrain C, Freeman M (2012) New lives for old: evolution of pseudoenzyme function illustrated by iRhoms. Nat Rev Mol Cell Biol. 13:489–98.
  5. ↑ Manning, G; Whyte, DB; Martinez, R; Hunter, T; Sudarsanam, S (2002). "The protein kinase complement of the human genome". Science. 298: 1912–34. doi:10.1126/science.1075762.
  6. ↑ Boudeau, J; Miranda-Saavedra, D; Barton, GJ; Alessi, DR (2006). "Emerging roles of pseudokinases". Trends Cell Biol. 16: 443–452. doi:10.1016/j.tcb.2006.07.003.
  7. ↑ Eyers PA, Keeshan K and Kannan N (2016) Tribbles in the 21st Century: The Evolving Roles of Tribbles Pseudokinases in Biology and Disease, Trends Cell Biol.
  8. ↑ Reiterer, V; Eyers, PA; Farhan, H (2014). "Day of the dead: pseudokinases and pseudophosphatases in physiology and disease". Trends Cell Biol. 24: 489–505. doi:10.1016/j.tcb.2014.03.008.
  9. ↑ Murphy, JM; Czabotar, PE; Hildebrand, JM; Lucet, IS; Zhang, JG; Alvarez-Diaz, S; Lewis, R; Lalaoui, N; Metcalf, D; Webb, AI; et al. (2013). "The pseudokinase MLKL mediates necroptosis via a molecular switch mechanism". Immunity. 39: 443–53. doi:10.1016/j.immuni.2013.06.018.
  10. ↑ Wishart, MJ; Dixon, JE (1998). "Gathering STYX: phosphatase-like form predicts functions for unique protein-interaction domains". Trends Biochem Sci. 23: 301–6. doi:10.1016/s0968-0004(98)01241-9.
  11. ↑ Reiterer, V; Eyers, PA; Farhan, H (2014). "Day of the dead: pseudokinases and pseudophosphatases in physiology and disease". Trends Cell Biol. 24: 489–505. doi:10.1016/j.tcb.2014.03.008.
  12. ↑ Chen, MJ; Dixon, JE; Manning, G (2017). "Genomics and evolution of protein phosphatases". Sci Signal. 10 (474): eaag1796. doi:10.1126/scisignal.aag1796.
  13. ↑ Zeqiraj, E; Tian, L; Piggott, CA; Pillon, MC; Duffy, NM; Ceccarelli, DF; Keszei, AF; Lorenzen, K; Kurinov, I; Orlicky, S; et al. (2015). "Higher-order assembly of BRCC36-KIAA0157 is required for DUB activity and biological function". Mol Cell. 59: 970–83. doi:10.1016/j.molcel.2015.07.028.
  14. ↑ Strickson, S; Emmerich, CH; Goh, ET; Zhang, J; Kelsall, IR; Macartney, T; Hastie, CJ; Knebel, A; Peggie, M; Marchesi, F; Arthur, JS; Cohen, P (2017). "Roles of the TRAF6 and Pellino E3 ligases in MyD88 and RANKL signaling". PNAS: 201702367. doi:10.1073/pnas.1702367114.
  15. ↑ Aggarwal-Howarth, S; Scott, JD (2017). "Pseudoscaffolds and anchoring proteins: the difference is in the details". Biochem Soc Trans. 45: 371–379. doi:10.1042/bst20160329.
  16. ↑ Foulkes, DM; Byrne, DP; Bailey, FP; Eyers, PA (2015). "Tribbles pseudokinases: novel targets for chemical biology and drug discovery?". Biochem Soc Trans. 43: 1095–103. doi:10.1042/bst20150109.
  17. ↑ Foulkes, DM; Byrne, DP; Eyers, PA (2017). "Pseudokinases: update on their functions and evaluation as new drug targets". Future Med Chem. 9 (2): 245–265.
  18. ↑ Murphy, JM; Farhan, H; Eyers, PA (2017). "Bio-Zombie: the rise of pseudoenzymes in biology". Biochem Soc Trans. 45: 537–544. PMID 28408493. doi:10.1042/bst20160400.
  19. ↑ "Conferences and events | Biochemical Society - Pseudoenzymes 2016: from Signalling Mechanisms to Disease". Biochemistry.org. 2016-09-14. Retrieved 2017-01-16.
  20. ↑ "Biochemical Society | Advancing Molecular Bioscience". Biochemistry.org. Retrieved 2017-01-16.
  21. ↑ Murphy, JM; Farhan, H; Eyers, PA (2017). "Bio-Zombie: the rise of pseudoenzymes in biology". Biochem Soc Trans. 45: 537–544. PMID 28408493. doi:10.1042/bst20160400.
  22. ↑ http://events.embo.org/coming-soon/index.php?EventID=w18-49. Missing or empty |title= (help)
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