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Specificity and catalysis hardwired at the RNA-protein interface in a translational proofreading enzyme.

<div class='caption-title'>Dispensable role of side chains in substrate discrimination.</div>
<div class='caption-title'>Domain organization of archaeal threonyl-tRNA synthetase (ThrRS) and deacylation activities of ApThrRS-2 and PabNTD.</div>
<div class='caption-title'>Substrate analogue binding in NTD.</div>
Ahmad S, Muthukumar S, Kuncha SK, Routh SB, Yerabham AS, Hussain T, Kamarthapu V, Kruparani SP, Sankaranarayanan R
OpenAccess logo Nat Commun 6 7552 (2015)
Related entries: 4rr6, 4rr7, 4rr8, 4rr9, 4rra, 4rrb, 4rrc, 4rrd, 4rrf, 4rrg, 4rrh, 4rri, 4rrj, 4rrk, 4rrl, 4rrm, 4rrq

Cited: 16 times
EuropePMC logo PMID: 26113036

Abstract

Proofreading modules of aminoacyl-tRNA synthetases are responsible for enforcing a high fidelity during translation of the genetic code. They use strategically positioned side chains for specifically targeting incorrect aminoacyl-tRNAs. Here, we show that a unique proofreading module possessing a D-aminoacyl-tRNA deacylase fold does not use side chains for imparting specificity or for catalysis, the two hallmark activities of enzymes. We show, using three distinct archaea, that a side-chain-stripped recognition site is fully capable of solving a subtle discrimination problem. While biochemical probing establishes that RNA plays the catalytic role, mechanistic insights from multiple high-resolution snapshots reveal that differential remodelling of the catalytic core at the RNA-peptide interface provides the determinants for correct proofreading activity. The functional crosstalk between RNA and protein elucidated here suggests how primordial enzyme functions could have emerged on RNA-peptide scaffolds before recruitment of specific side chains.

Articles - 4rrr mentioned but not cited (3)

  1. Specificity and catalysis hardwired at the RNA-protein interface in a translational proofreading enzyme. Ahmad S, Muthukumar S, Kuncha SK, Routh SB, Yerabham AS, Hussain T, Kamarthapu V, Kruparani SP, Sankaranarayanan R. Nat Commun 6 7552 (2015)
  2. Contrasting use of CCR5 structural determinants by R5 and R5X4 variants within a human immunodeficiency virus type 1 primary isolate quasispecies. Yi Y, Singh A, Shaheen F, Louden A, Lee C, Collman RG. J Virol 77 12057-12066 (2003)
  3. Blocking Respiratory Syncytial Virus Entry: A Story with Twists. Weisshaar M, Cox R, Plemper RK. DNA Cell Biol 34 505-510 (2015)


Reviews citing this publication (4)

  1. Evolutionary Limitation and Opportunities for Developing tRNA Synthetase Inhibitors with 5-Binding-Mode Classification. Fang P, Guo M. Life (Basel) 5 1703-1725 (2015)
  2. Chiral checkpoints during protein biosynthesis. Kuncha SK, Kruparani SP, Sankaranarayanan R. J Biol Chem 294 16535-16548 (2019)
  3. Recent Updates on DTD (D-Tyr-tRNA(Tyr) Deacylase): An Enzyme Essential for Fidelity and Quality of Protein Synthesis. Bhatt TK, Soni R, Sharma D. Front Cell Dev Biol 4 32 (2016)
  4. Small Molecule Catalysts with Therapeutic Potential. Ney Y, Jawad Nasim M, Kharma A, Youssef LA, Jacob C. Molecules 23 E765 (2018)

Articles citing this publication (9)

  1. A chiral selectivity relaxed paralog of DTD for proofreading tRNA mischarging in Animalia. Kuncha SK, Mazeed M, Singh R, Kattula B, Routh SB, Sankaranarayanan R. Nat Commun 9 511 (2018)
  2. Role of D-aminoacyl-tRNA deacylase beyond chiral proofreading as a cellular defense against glycine mischarging by AlaRS. Pawar KI, Suma K, Seenivasan A, Kuncha SK, Routh SB, Kruparani SP, Sankaranarayanan R. Elife 6 e24001 (2017)
  3. Elongation Factor Tu Prevents Misediting of Gly-tRNA(Gly) Caused by the Design Behind the Chiral Proofreading Site of D-Aminoacyl-tRNA Deacylase. Routh SB, Pawar KI, Pawar KI, Ahmad S, Singh S, Suma K, Kumar M, Kuncha SK, Yadav K, Kruparani SP, Sankaranarayanan R. PLoS Biol 14 e1002465 (2016)
  4. Discovery and Investigation of Natural Editing Function against Artificial Amino Acids in Protein Translation. Völler JS, Dulic M, Gerling-Driessen UI, Biava H, Baumann T, Budisa N, Gruic-Sovulj I, Koksch B. ACS Cent Sci 3 73-80 (2017)
  5. An RNA Binding Peptide Consisting of Four Types of Amino Acid by in Vitro Selection Using cDNA Display. Kumachi S, Husimi Y, Nemoto N. ACS Omega 1 52-57 (2016)
  6. A revised mechanism for (p)ppGpp synthesis by Rel proteins: The critical role of the 2'-OH of GTP. Patil PR, Vithani N, Singh V, Kumar A, Prakash B. J Biol Chem 295 12851-12867 (2020)
  7. Indirect Routes to Aminoacyl-tRNA: The Diversity of Prokaryotic Cysteine Encoding Systems. Mukai T, Amikura K, Fu X, Söll D, Crnković A. Front Genet 12 794509 (2021)
  8. CAT-Site: Predicting Protein Binding Sites Using a Convolutional Neural Network. Petrovski ŽH, Hribar-Lee B, Bosnić Z. Pharmaceutics 15 119 (2022)
  9. Negative catalysis by the editing domain of class I aminoacyl-tRNA synthetases. Zivkovic I, Ivkovic K, Cvetesic N, Marsavelski A, Gruic-Sovulj I. Nucleic Acids Res 50 4029-4041 (2022)


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