Pseudoenzymes

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Pseudoenzymes are variants of enzymes without enzyme activity .

properties

Pseudoenzymes contain mutations that lead to a loss of catalytic activity. They occur in all realms of life. Bioinformatic genome analyzes suggest that pseudoenzymes occur in all enzyme families. They play an important role in the regulation of various metabolic processes, as well as in the regulation of signal transduction cascades . The best studied and therefore best understood pseudoenzymes in terms of structure and biological function are the pseudokinases, pseudoesterases and pseudophosphatases. About 10% of the protein kinases in humans and mice are pseudoenzymes. About 60 pseudoprotein kinases are known in humans.

Differences in the sequence of enzymes and their inactive homologues were identified and investigated early on. Some of the earlier work also referred to pseudoenzymes as "Prozyme". Pseudoenzymes have been found in various enzyme families such as proteases , protein kinases , phosphatases, and ubiquitin- modifying enzymes. The role of pseudoenzymes as so-called “pseudo scaffolds” was also discussed.

The cytomegalovirus uses a pseudoenzyme to inactivate RIG-I and thus act as a virulence factor .

Types

Type function Examples
Pseudokinases Allosteric regulation of the corresponding protein kinase STRADα regulates LKB1, Raf regulates JAK1-3 and TYK2 at their C-terminal tyrosine kinase protein domains via its KSR1 / 2 domain
Pseudokinases Allosteric regulation of other enzymes VRK3 regulates VHR
Pseudokinases Protein-protein interaction MLKL pseudokinase regulates the exposure of the four-helix-bundle protein domain and the binding of HSP90 : Cdc37
Pseudokinases Scaffold protein of signal complexes Tribbles regulates the binding of (C / EBPα) to the E3 ubiquitin ligase COP1
Pseudo-histidine kinases Protein-protein interaction Caulobacter sp. DivL binds phosphorylated DivK, whereby DivL inhibits the kinase CckA in the cell cycle
Pseudophosphatases competitive inhibition EGG-4 / EGG-5 regulates MBK-2 , STYX competes with DUSP4 for binding to ERK1 / 2
Pseudophosphatases Allosteric inhibition of phosphatases MTMR13 binds and activates MTMR2
Pseudophosphatases Regulation of protein transport STYX binds ERK1 / 2 in the cell nucleus
Pseudophosphatases Regulation of signal complexes STYX binds FBXW7 to inhibit its binding to the SCF-ubiquitin ligase complex
Pseudoproteases Allosteric regulation of proteases cFLIP inhibits caspase-8
Pseudoproteases Protein transport iRhom proteins
Pseudodeubiquitinases (pseudoDUB) Allosteric regulation of the DUB KIAA0157 forms a complex with DUB and BRCC36
Pseudoligases (pseudo-ubiquitin E2) Allosteric regulation of the E2 ligases Mms2 binds Ubc13 and regulates binding to K63

Applications

Pseudoenzymes are being investigated as therapeutic targets.

Conferences and international cooperation

The field of pseudoenzymes is still young. The first conference on pseudoenzymes was held in Liverpool in 2016 and was sponsored by the Biochemical Society . The conference was a success, which is why a second conference will take place in May 2018 and will be sponsored by EMBO (European Molecular Biology Organization).

Individual evidence

  1. ↑ a b c J. M. Murphy, H. Farhan, PA Eyers: Bio-Zombie: the rise of pseudoenzymes in biology. In: Biochemical Society transactions. Volume 45, number 2, April 2017, pp. 537-544, doi : 10.1042 / BST20160400 , PMID 28408493 .
  2. ^ PA Eyers, JM Murphy: The evolving world of pseudoenzymes: proteins, prejudice and zombies . In: BMC Biol. . 14, 2016, p. 98. doi : 10.1186 / s12915-016-0322-x .
  3. ^ V Reiterer, PA Eyers, H Farhan: Day of the dead: pseudokinases and pseudophosphatases in physiology and disease . In: Trends Cell Biol . 24, 2014, pp. 489-505. doi : 10.1016 / j.tcb.2014.03.008 .
  4. ^ AV Jacobsen, JM Murphy: The secret life of kinases: insights into non-catalytic signaling functions from pseudokinases. In: Biochemical Society transactions. Volume 45, number 3, June 2017, pp. 665-681, doi : 10.1042 / BST20160331 , PMID 28620028 .
  5. ^ A b D. P. Byrne, DM Foulkes, PA Eyers: Pseudokinases: update on their functions and evaluation as new drug targets. In: Future medicinal chemistry. Volume 9, Number 2, January 2017, pp. 245-265, doi : 10.4155 / fmc-2016-0207 , PMID 28097887 .
  6. ^ AE Todd, CA Orengo, JM Thornton: Sequence and structural differences between enzymes and nonenzyme homologs . In: Structure . 10, 2002, pp. 1435-51. doi : 10.1016 / s0969-2126 (02) 00861-4 .
  7. ^ EK Willert, MA Phillips: Allosteric regulation of an essential trypanosome polyamine biosynthetic enzyme by a catalytically dead homolog . In: Proc. Natl. Acad. Sci. USA . 104, 2007, pp. 8275-8280. doi : 10.1073 / pnas.0701111104 .
  8. ^ Adrain C, Freeman M (2012) New lives for old: evolution of pseudoenzyme function illustrated by iRhoms. Nat Rev Mol Cell Biol. 13: 489-98.
  9. ^ G Manning, DB Whyte, R Martinez, T Hunter, S Sudarsanam: The protein kinase complement of the human genome . In: Science . 298, 2002, pp. 1912-34. doi : 10.1126 / science.1075762 .
  10. ↑ J Boudeau, D Miranda-Saavedra, GJ Barton, DR Alessi: Emerging roles of pseudo kinases . In: Trends Cell Biol . 16, 2006, pp. 443-452. doi : 10.1016 / j.tcb.2006.07.003 .
  11. ↑ 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.
  12. ^ V Reiterer, PA Eyers, H Farhan: Day of the dead: pseudokinases and pseudophosphatases in physiology and disease . In: Trends Cell Biol . 24, 2014, pp. 489-505. doi : 10.1016 / j.tcb.2014.03.008 .
  13. ↑ JM Murphy, PE Czabotar, JM Hildebrand, IS Lucet, JG Zhang, S Alvarez-Diaz, R Lewis, N Lalaoui, D Metcalf, AI Webb, et al .: The pseudokinase MLKL mediates necroptosis via a molecular switch mechanism . In: Immunity . 39, 2013, pp. 443-53. doi : 10.1016 / j.immuni.2013.06.018 .
  14. ↑ MJ Wishart, JE Dixon: Gathering STYX: phosphatase-like form predicts functions for unique protein-interaction domains . In: Trends Biochem Sci . 23, 1998, pp. 301-6. doi : 10.1016 / s0968-0004 (98) 01241-9 .
  15. ^ V Reiterer, PA Eyers, H Farhan: Day of the dead: pseudokinases and pseudophosphatases in physiology and disease . In: Trends Cell Biol . 24, 2014, pp. 489-505. doi : 10.1016 / j.tcb.2014.03.008 .
  16. ↑ MJ Chen, JE Dixon, G Manning: Genomics and evolution of protein phosphatases . In: Sci Signal . 10, No. 474, 2017, p. Eaag1796. doi : 10.1126 / scisignal.aag1796 .
  17. ↑ E Zeqiraj, L Tian, CA Piggott, MC Pillon, NM Duffy, DF Ceccarelli, AF Keszei, K Lorenzen, I Kurinov, S Orlicky: Higher-order assembly of BRCC36-KIAA0157 is required for DUB activity and biological function . In: Mol Cell . 59, 2015, pp. 970-83. doi : 10.1016 / j.molcel.2015.07.028 .
  18. ↑ S Strickson, CH Emmerich, ET Goh, J Zhang, IR Kelsall, T Macartney, CJ Hastie, A Knebel, M Peggie, F Marchesi, JS Arthur, P Cohen: Roles of the TRAF6 and Pellino E3 ligases in MyD88 and RANKL signaling . In: PNAS . 2017, S. 201702367. doi : 10.1073 / pnas.1702367114 .
  19. ^ S. Aggarwal-Howarth, JD Scott: Pseudoscaffolds and anchoring proteins: the difference is in the details . In: Biochem Soc Trans . 45, 2017, pp. 371-379. doi : 10.1042 / bst20160329 .
  20. ↑ D. Kolakofsky, D. Garcin: γHV68 vGAT: a viral pseudoenzyme pimping for PAMPs. In: Molecular cell. Volume 58, number 1, April 2015, pp. 3–4, doi : 10.1016 / j.molcel.2015.03.021 , PMID 25839430 .
  21. ^ DM Foulkes, DP Byrne, FP Bailey, PA Eyers: Tribbles pseudokinases: novel targets for chemical biology and drug discovery? . In: Biochem Soc Trans . 43, 2015, pp. 1095-103. doi : 10.1042 / bst20150109 .
  22. ^ DM Foulkes, DP Byrne, PA Eyers: Pseudokinases: update on their functions and evaluation as new drug targets . In: Future Med Chem. . 9, No. 2, 2017, pp. 245-265.
  23. ↑ “Conferences and events | Biochemical Society - Pseudoenzymes 2016: from Signaling Mechanisms to Disease” , on Biochemistry.org, January 16, 2017.
  24. ↑ http://events.embo.org/coming-soon/index.php?EventID=w18-49 . Retrieved on 2017-06-27