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Crystal structure of the VapBC-15 complex from Mycobacterium tuberculosis reveals a two-metal ion dependent PIN-domain ribonuclease and a variable mode of toxin-antitoxin assembly.

Das U, Pogenberg V, Subhramanyam UK, Wilmanns M, Gourinath S, Srinivasan A
J Struct Biol 188 249-58 (2014)
Cited: 34 times
EuropePMC logo PMID: 25450593

Abstract

Although PIN (PilT N-terminal)-domain proteins are known to have ribonuclease activity, their specific mechanism of action remains unknown. VapCs form a family of ribonucleases that possess a PIN-domain assembly and are known as toxins. The activities of VapCs are impaired by VapB antitoxins. Here we present the crystal structure of the VapBC-15 toxin-antitoxin complex from Mycobacterium tuberculosis determined to 2.1Å resolution. The VapB-15 and VapC-15 components assemble into one heterotetramer (VapB2C2) and two heterotrimers (VapBC2) in each asymmetric unit of the crystal. The active site of VapC-15 toxin consists of a cluster of acidic amino acid residues and two divalent metal ions, forming a well organised ribonuclease active site. The distribution of the catalytic-site residues of the VapC-15 toxin is similar to that of T4 RNase H and of Methanococcus jannaschii FEN-1, providing strong evidence that these three proteins share a similar mechanism of activity. The presence of both VapB2C2 and VapBC2 emphasizes the fact that the same antitoxin can bind the toxin in 1:1 and 1:2 ratios. The crystal structure determination of the VapBC-15 complex reveals for the first time a PIN-domain ribonuclease protein that shows two metal ions at the active site and a variable mode of toxin-antitoxin assembly. The structure further shows that VapB-15 antitoxin binds to the same groove meant for the binding of putative substrate (RNA), resulting in the inhibition of VapC-15's toxicity.

Reviews - 4chg mentioned but not cited (5)

  1. Structure, Biology, and Therapeutic Application of Toxin-Antitoxin Systems in Pathogenic Bacteria. Lee KY, Lee BJ. Toxins (Basel) 8 (2016)
  2. Wake me when it's over - Bacterial toxin-antitoxin proteins and induced dormancy. Coussens NP, Daines DA. Exp. Biol. Med. (Maywood) 241 1332-1342 (2016)
  3. Structural conservation of the PIN domain active site across all domains of life. Senissar M, Manav MC, Brodersen DE. Protein Sci. 26 1474-1492 (2017)
  4. A Systematic Overview of Type II and III Toxin-Antitoxin Systems with a Focus on Druggability. Kang SM, Kim DH, Jin C, Lee BJ. Toxins (Basel) 10 (2018)
  5. Focused Overview of Mycobacterium tuberculosis VapBC Toxin-Antitoxin Systems Regarding Their Structural and Functional Aspects: Including Insights on Biomimetic Peptides. Kang SM. Biomimetics (Basel) 8 412 (2023)

Articles - 4chg mentioned but not cited (8)

  1. Structural and functional studies of the Mycobacterium tuberculosis VapBC30 toxin-antitoxin system: implications for the design of novel antimicrobial peptides. Lee IG, Lee SJ, Chae S, Lee KY, Kim JH, Lee BJ. Nucleic Acids Res. 43 7624-7637 (2015)
  2. Comprehensive classification of the PIN domain-like superfamily. Matelska D, Steczkiewicz K, Ginalski K. Nucleic Acids Res. 45 6995-7020 (2017)
  3. VapC21 Toxin Contributes to Drug-Tolerance and Interacts With Non-cognate VapB32 Antitoxin in Mycobacterium tuberculosis. Sharma A, Chattopadhyay G, Chopra P, Bhasin M, Thakur C, Agarwal S, Ahmed S, Chandra N, Varadarajan R, Singh R. Front Microbiol 11 2037 (2020)
  4. Functional details of the Mycobacterium tuberculosis VapBC26 toxin-antitoxin system based on a structural study: insights into unique binding and antibiotic peptides. Kang SM, Kim DH, Lee KY, Park SJ, Yoon HJ, Lee SJ, Im H, Lee BJ. Nucleic Acids Res. 45 8564-8580 (2017)
  5. Potential Efficacy of β-Amyrin Targeting Mycobacterial Universal Stress Protein by In Vitro and In Silico Approach. Beg MA, Shivangi, Afzal O, Akhtar MS, Altamimi ASA, Hussain A, Imam MA, Ahmad MN, Chopra S, Athar F. Molecules 27 4581 (2022)
  6. The VapBC1 toxin-antitoxin complex from Mycobacterium tuberculosis: purification, crystallization and X-ray diffraction analysis. Lu Z, Wang H, Zhang A, Tan Y. Acta Crystallogr F Struct Biol Commun 72 485-489 (2016)
  7. Mycobacterium tuberculosis Rv0229c Shows Ribonuclease Activity and Reveals Its Corresponding Role as Toxin VapC51. Kang SM. Antibiotics (Basel) 12 840 (2023)
  8. Molecular and Structural Basis of Cross-Reactivity in M. tuberculosis Toxin-Antitoxin Systems. Tandon H, Melarkode Vattekatte A, Srinivasan N, Sandhya S. Toxins (Basel) 12 (2020)


Reviews citing this publication (3)

  1. Keeping the Wolves at Bay: Antitoxins of Prokaryotic Type II Toxin-Antitoxin Systems. Chan WT, Espinosa M, Yeo CC. Front Mol Biosci 3 9 (2016)
  2. RNA damage in biological conflicts and the diversity of responding RNA repair systems. Burroughs AM, Aravind L. Nucleic Acids Res. 44 8525-8555 (2016)
  3. The Variety in the Common Theme of Translation Inhibition by Type II Toxin-Antitoxin Systems. Jurėnas D, Van Melderen L. Front Genet 11 262 (2020)

Articles citing this publication (18)

  1. VapCs of Mycobacterium tuberculosis cleave RNAs essential for translation. Winther K, Tree JJ, Tollervey D, Gerdes K. Nucleic Acids Res. 44 9860-9871 (2016)
  2. Structural Determinants for Antitoxin Identity and Insulation of Cross Talk between Homologous Toxin-Antitoxin Systems. Walling LR, Butler JS. J. Bacteriol. 198 3287-3295 (2016)
  3. Structure-function analysis of VapB4 antitoxin identifies critical features of a minimal VapC4 toxin-binding module. Jin G, Pavelka MS, Butler JS. J. Bacteriol. 197 1197-1207 (2015)
  4. Bioinformatic and mutational studies of related toxin-antitoxin pairs in Mycobacterium tuberculosis predict and identify key functional residues. Tandon H, Sharma A, Wadhwa S, Varadarajan R, Singh R, Srinivasan N, Sandhya S. J Biol Chem 294 9048-9063 (2019)
  5. Structure and Function of a Novel ATPase that Interacts with Holliday Junction Resolvase Hjc and Promotes Branch Migration. Zhai B, DuPrez K, Doukov TI, Li H, Huang M, Shang G, Ni J, Gu L, Shen Y, Fan L. J. Mol. Biol. 429 1009-1029 (2017)
  6. Crystal structure of Mycobacterium tuberculosis VapC20 toxin and its interactions with cognate antitoxin, VapB20, suggest a model for toxin-antitoxin assembly. Deep A, Kaundal S, Agarwal S, Singh R, Thakur KG. FEBS J. 284 4066-4082 (2017)
  7. Structural analysis of the active site architecture of the VapC toxin from Shigella flexneri. Xu K, Dedic E, Brodersen DE. Proteins 84 892-899 (2016)
  8. System-Wide Analysis Unravels the Differential Regulation and In Vivo Essentiality of Virulence-Associated Proteins B and C Toxin-Antitoxin Systems of Mycobacterium tuberculosis. Agarwal S, Tiwari P, Deep A, Kidwai S, Gupta S, Thakur KG, Singh R. J. Infect. Dis. 217 1809-1820 (2018)
  9. Toxin inhibition in C. crescentus VapBC1 is mediated by a flexible pseudo-palindromic protein motif and modulated by DNA binding. Bendtsen KL, Xu K, Luckmann M, Winther KS, Shah SA, Pedersen CNS, Brodersen DE. Nucleic Acids Res. 45 2875-2886 (2017)
  10. Structural, functional and biological insights into the role of Mycobacterium tuberculosis VapBC11 toxin-antitoxin system: targeting a tRNase to tackle mycobacterial adaptation. Deep A, Tiwari P, Agarwal S, Kaundal S, Kidwai S, Singh R, Thakur KG. Nucleic Acids Res. 46 11639-11655 (2018)
  11. The Cysteine Protease MaOC1, a Prokaryotic Caspase Homolog, Cleaves the Antitoxin of a Type II Toxin-Antitoxin System. Klemenčič M, Halužan Vasle A, Dolinar M. Front Microbiol 12 635684 (2021)
  12. VapC proteins from Mycobacterium tuberculosis share ribonuclease sequence specificity but differ in regulation and toxicity. Sharrock A, Ruthe A, Andrews ESV, Arcus VA, Hicks JL. PLoS ONE 13 e0203412 (2018)
  13. Functional Studies of Five Toxin-Antitoxin Modules in Mycobacterium tuberculosis H37Rv. Kim Y, Choi E, Hwang J. Front Microbiol 7 2071 (2016)
  14. Functional and Biochemical Characterization of the MazEF6 Toxin-Antitoxin System of Mycobacterium tuberculosis. Chattopadhyay G, Bhasin M, Ahmed S, Gosain TP, Ganesan S, Das S, Thakur C, Chandra N, Singh R, Varadarajan R. J Bacteriol 204 e0005822 (2022)
  15. HEPN RNases - an emerging class of functionally distinct RNA processing and degradation enzymes. Pillon MC, Gordon J, Frazier MN, Stanley RE. Crit Rev Biochem Mol Biol 56 88-108 (2021)
  16. Resonance assignments of a VapC family toxin from Clostridium thermocellum. Wang C, Xuan J, Cui Q, Feng Y. Biomol NMR Assign 10 367-371 (2016)
  17. Stay or Go: Sulfolobales Biofilm Dispersal Is Dependent on a Bifunctional VapB Antitoxin. Lewis AM, Willard DJ, H Manesh MJ, Sivabalasarma S, Albers SV, Kelly RM. mBio 14 e0005323 (2023)
  18. Structural characterization of VapB46 antitoxin from Mycobacterium tuberculosis: insights into VapB46-DNA binding. Roy M, Kundu A, Bhunia A, Das Gupta S, De S, Das AK. FEBS J 286 1174-1190 (2019)


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