5d0v › Citations

A unified mechanism for proteolysis and autocatalytic activation in the 20S proteasome.

Huber EM, Heinemeyer W, Li X, Arendt CS, Hochstrasser M, Groll M
Nat Commun 7 10900 (2016)
Related entries: 5cz4, 5cz5, 5cz6, 5cz7, 5cz8, 5cz9, 5cza, 5d0s, 5d0t, 5d0w, 5d0x, 5d0z, 5fg7, 5fg9, 5fga, 5fgd, 5fge, 5fgf, 5fgg, 5fgh, 5fgi, 5fhs

Cited: 48 times
EuropePMC logo PMID: 26964885

Abstract

Biogenesis of the 20S proteasome is tightly regulated. The N-terminal propeptides protecting the active-site threonines are autocatalytically released only on completion of assembly. However, the trigger for the self-activation and the reason for the strict conservation of threonine as the active site nucleophile remain enigmatic. Here we use mutagenesis, X-ray crystallography and biochemical assays to suggest that Lys33 initiates nucleophilic attack of the propeptide by deprotonating the Thr1 hydroxyl group and that both residues together with Asp17 are part of a catalytic triad. Substitution of Thr1 by Cys disrupts the interaction with Lys33 and inactivates the proteasome. Although a Thr1Ser mutant is active, it is less efficient compared with wild type because of the unfavourable orientation of Ser1 towards incoming substrates. This work provides insights into the basic mechanism of proteolysis and propeptide autolysis, as well as the evolutionary pressures that drove the proteasome to become a threonine protease.

Reviews citing this publication (17)

  1. Proteasome Structure and Assembly. Budenholzer L, Cheng CL, Li Y, Hochstrasser M. J Mol Biol 429 3500-3524 (2017)
  2. Dynamic Regulation of the 26S Proteasome: From Synthesis to Degradation. Marshall RS, Vierstra RD. Front Mol Biosci 6 40 (2019)
  3. Bacterial proteases, untapped antimicrobial drug targets. Culp E, Wright GD. J Antibiot (Tokyo) 70 366-377 (2017)
  4. Structure, Dynamics and Function of the 26S Proteasome. Mao Y. Subcell Biochem 96 1-151 (2021)
  5. Effects of Glycosylation on the Enzymatic Activity and Mechanisms of Proteases. Goettig P. Int J Mol Sci 17 E1969 (2016)
  6. Structural Insights into Substrate Recognition and Processing by the 20S Proteasome. Sahu I, Glickman MH. Biomolecules 11 148 (2021)
  7. Bacterial Proteasomes: Mechanistic and Functional Insights. Becker SH, Darwin KH. Microbiol Mol Biol Rev 81 e00036-16 (2017)
  8. Proteasome Activation to Combat Proteotoxicity. Jones CL, Tepe JJ. Molecules 24 E2841 (2019)
  9. Ubiquitination and the Proteasome as Drug Targets in Trypanosomatid Diseases. Bijlmakers MJ. Front Chem 8 630888 (2020)
  10. Proteasome dynamics between proliferation and quiescence stages of Saccharomyces cerevisiae. Yedidi RS, Fatehi AK, Enenkel C. Crit Rev Biochem Mol Biol 51 497-512 (2016)
  11. A Nut for Every Bolt: Subunit-Selective Inhibitors of the Immunoproteasome and Their Therapeutic Potential. Huber EM, Groll M. Cells 10 1929 (2021)
  12. Advances in Proteasome Enhancement by Small Molecules. George DE, Tepe JJ. Biomolecules 11 1789 (2021)
  13. Functional Differences between Proteasome Subtypes. Abi Habib J, Lesenfants J, Vigneron N, Van den Eynde BJ. Cells 11 421 (2022)
  14. Biology and Biochemistry of Bacterial Proteasomes. Becker SH, Li H, Li H, Heran Darwin K. Subcell Biochem 93 339-358 (2019)
  15. Chaperone-mediated assembly of the proteasome core particle - recent developments and structural insights. Schnell HM, Walsh RM, Rawson S, Hanna J. J Cell Sci 135 jcs259622 (2022)
  16. The Human Ntn-Hydrolase Superfamily: Structure, Functions and Perspectives. Linhorst A, Lübke T. Cells 11 1592 (2022)
  17. The Molecular Mechanisms Governing the Assembly of the Immuno- and Thymoproteasomes in the Presence of Constitutive Proteasomes. Watanabe A, Yashiroda H, Ishihara S, Lo M, Murata S. Cells 11 1580 (2022)

Articles citing this publication (31)

  1. Structural insights into the functional cycle of the ATPase module of the 26S proteasome. Wehmer M, Rudack T, Beck F, Aufderheide A, Pfeifer G, Plitzko JM, Förster F, Schulten K, Baumeister W, Sakata E. Proc Natl Acad Sci U S A 114 1305-1310 (2017)
  2. The inhibition mechanism of human 20S proteasomes enables next-generation inhibitor design. Schrader J, Henneberg F, Mata RA, Tittmann K, Schneider TR, Stark H, Bourenkov G, Chari A. Science 353 594-598 (2016)
  3. Molecular Mechanisms of the Cardiotoxicity of the Proteasomal-Targeted Drugs Bortezomib and Carfilzomib. Hasinoff BB, Patel D, Wu X. Cardiovasc Toxicol 17 237-250 (2017)
  4. The proteasome as a druggable target with multiple therapeutic potentialities: Cutting and non-cutting edges. Tundo GR, Sbardella D, Santoro AM, Coletta A, Oddone F, Grasso G, Milardi D, Lacal PM, Marini S, Purrello R, Graziani G, Coletta M. Pharmacol Ther 213 107579 (2020)
  5. Discovery of the First-in-Class Dual Histone Deacetylase-Proteasome Inhibitor. Bhatia S, Krieger V, Groll M, Osko JD, Reßing N, Ahlert H, Borkhardt A, Kurz T, Christianson DW, Hauer J, Hansen FK. J Med Chem 61 10299-10309 (2018)
  6. Global analysis of biosynthetic gene clusters reveals conserved and unique natural products in entomopathogenic nematode-symbiotic bacteria. Shi YM, Hirschmann M, Shi YN, Ahmed S, Abebew D, Tobias NJ, Grün P, Crames JJ, Pöschel L, Kuttenlochner W, Richter C, Herrmann J, Müller R, Thanwisai A, Pidot SJ, Stinear TP, Groll M, Kim Y, Bode HB. Nat Chem 14 701-712 (2022)
  7. A humanized yeast proteasome identifies unique binding modes of inhibitors for the immunosubunit β5i. Huber EM, Heinemeyer W, de Bruin G, Overkleeft HS, Groll M. EMBO J 35 2602-2613 (2016)
  8. Molecular mechanism of activation of the immunoregulatory amidase NAAA. Gorelik A, Gebai A, Illes K, Piomelli D, Nagar B. Proc Natl Acad Sci U S A 115 E10032-E10040 (2018)
  9. The Proteasome as a Drug Target in the Metazoan Pathogen, Schistosoma mansoni. Bibo-Verdugo B, Wang SC, Almaliti J, Ta AP, Jiang Z, Wong DA, Lietz CB, Suzuki BM, El-Sakkary N, Hook V, Salvesen GS, Gerwick WH, Caffrey CR, O'Donoghue AJ. ACS Infect Dis 5 1802-1812 (2019)
  10. Structural Elucidation of a Nonpeptidic Inhibitor Specific for the Human Immunoproteasome. Cui H, Baur R, Le Chapelain C, Dubiella C, Heinemeyer W, Huber EM, Groll M. Chembiochem 18 523-526 (2017)
  11. Structure-Based Design of Inhibitors Selective for Human Proteasome β2c or β2i Subunits. Xin BT, Huber EM, de Bruin G, Heinemeyer W, Maurits E, Espinal C, Du Y, Janssens M, Weyburne ES, Kisselev AF, Florea BI, Driessen C, van der Marel GA, Groll M, Overkleeft HS. J Med Chem 62 1626-1642 (2019)
  12. Potential of Zimbabwean commercial probiotic products and strains of Lactobacillus plantarum as prophylaxis and therapy against diarrhoea caused by Escherichia coli in children. Chingwaru W, Vidmar J. Asian Pac J Trop Med 10 57-63 (2017)
  13. Towards Selective Mycobacterial ClpP1P2 Inhibitors with Reduced Activity against the Human Proteasome. Moreira W, Santhanakrishnan S, Ngan GJY, Low CB, Sangthongpitag K, Poulsen A, Dymock BW, Dick T. Antimicrob Agents Chemother 61 e02307-16 (2017)
  14. Activation, Structure, Biosynthesis and Bioactivity of Glidobactin-like Proteasome Inhibitors from Photorhabdus laumondii. Zhao L, Le Chapelain C, Brachmann AO, Kaiser M, Groll M, Bode HB. Chembiochem 22 1582-1588 (2021)
  15. Defective immuno- and thymoproteasome assembly causes severe immunodeficiency. Treise I, Huber EM, Klein-Rodewald T, Heinemeyer W, Grassmann SA, Basler M, Adler T, Rathkolb B, Helming L, Andres C, Klaften M, Landbrecht C, Wieland T, Strom TM, McCoy KD, Macpherson AJ, Wolf E, Groettrup M, Ollert M, Neff F, Gailus-Durner V, Fuchs H, Hrabě de Angelis M, Groll M, Busch DH. Sci Rep 8 5975 (2018)
  16. Archaeal Connectase is a specific and efficient protein ligase related to proteasome β subunits. Fuchs ACD, Ammelburg M, Martin J, Schmitz RA, Hartmann MD, Lupas AN. Proc Natl Acad Sci U S A 118 e2017871118 (2021)
  17. Structural characterization of the bacterial proteasome homolog BPH reveals a tetradecameric double-ring complex with unique inner cavity properties. Fuchs ACD, Maldoner L, Hipp K, Hartmann MD, Martin J. J Biol Chem 293 920-930 (2018)
  18. A Marine Diterpenoid Modulates the Proteasome Activity in Murine Macrophages Stimulated with LPS. González Y, Doens D, Cruz H, Santamaría R, Gutiérrez M, Llanes A, Fernández PL. Biomolecules 8 E109 (2018)
  19. Myocyte-Damaging Effects and Binding Kinetics of Boronic Acid and Epoxyketone Proteasomal-Targeted Drugs. Hasinoff BB, Patel D. Cardiovasc Toxicol 18 557-568 (2018)
  20. Proteasome Inhibition Is an Effective Treatment Strategy for Microsporidia Infection in Honey Bees. Huntsman EM, Cho RM, Kogan HV, McNamara-Bordewick NK, Tomko RJ, Snow JW. Biomolecules 11 1600 (2021)
  21. Tunable Probes with Direct Fluorescence Signals for the Constitutive and Immunoproteasome. Dubiella C, Cui H, Groll M. Angew Chem Int Ed Engl 55 13330-13334 (2016)
  22. (-)-Homosalinosporamide A and Its Mode of Proteasome Inhibition: An X-ray Crystallographic Study. Groll M, Nguyen H, Vellalath S, Romo D. Mar Drugs 16 E240 (2018)
  23. Cleavage-Dependent Activation of ATP-Dependent Protease HslUV from Staphylococcus aureus. Jeong S, Ahn J, Kwon AR, Ha NC. Mol Cells 43 694-704 (2020)
  24. Cooperativity in Proteasome Core Particle Maturation. Suppahia A, Itagi P, Burris A, Kim FMG, Vontz A, Kante A, Kim S, Im W, Deeds EJ, Roelofs J. iScience 23 101090 (2020)
  25. Design, synthesis, and evaluation of cystargolide-based β-lactones as potent proteasome inhibitors. Niroula D, Hallada LP, Le Chapelain C, Ganegamage SK, Dotson D, Rogelj S, Groll M, Tello-Aburto R. Eur J Med Chem 157 962-977 (2018)
  26. Inhibition of the proteasome activity by graphene oxide contributes to its cytotoxicity. Ma X, Lee S, Fei X, Fang G, Huynh T, Chong Y, Chai Z, Ge C, Zhou R. Nanotoxicology 12 185-200 (2018)
  27. Structure of the reduced microsporidian proteasome bound by PI31-like peptides in dormant spores. Jespersen N, Ehrenbolger K, Winiger RR, Svedberg D, Vossbrinck CR, Barandun J. Nat Commun 13 6962 (2022)
  28. An astonishing wealth of new proteasome homologs. Fuchs ACD, Alva V, Lupas AN. Bioinformatics 37 4694-4703 (2021)
  29. Covalent Inhibition of the Human 20S Proteasome with Homobelactosin C Inquired by QM/MM Studies. Serrano-Aparicio N, Ferrer S, Świderek K. Pharmaceuticals (Basel) 15 531 (2022)
  30. Insight into Inhibitor Binding in the Eukaryotic Proteasome: Computations of the 20S CP. Hodošček M, Elghobashi-Meinhardt N. Int J Mol Sci 19 3858 (2018)
  31. The proteasome beta 5 subunit is essential for sexually divergent adaptive homeostatic responses to oxidative stress in D. melanogaster. Pomatto LCD, Sisliyan C, Wong S, Cline M, Tower J, Davies KJA. Free Radic Biol Med 160 67-77 (2020)


Quick links