Refolding of lid subdomain of SARS-CoV-2 nsp14 upon nsp10 interaction releases exonuclease activity

Anna Czarna, Jacek Plewka, Leanid Kresik, Alex Matsuda, Abdulkarim Karim, Colin Robinson, Sean O'Byrne, Fraser Cunningham, Irene Georgiou, Piotr Wilk, Magdalena Pachota, Grzegorz Popowicz, Paul Graham Wyatt (Lead / Corresponding author), Grzegorz Dubin (Lead / Corresponding author), Krzysztof Pyrć (Lead / Corresponding author)

Research output: Contribution to journalArticlepeer-review

3 Citations (Scopus)
17 Downloads (Pure)

Abstract

During RNA replication, coronaviruses require proofreading to maintain the integrity of their large genomes. Nsp14 associates with viral polymerase complex to excise the mismatched nucleotides. Aside from the exonuclease activity, nsp14 methyltransferase domain mediates cap methylation, facilitating translation initiation and protecting viral RNA from recognition by the innate immune sensors. The nsp14 exonuclease activity is modulated by a protein co-factor nsp10. While the nsp10/nsp14 complex structure is available, the mechanistic basis for nsp10-mediated modulation remains unclear in the absence of the nsp14 structure. Here, we provide a crystal structure of nsp14 in an apo-form. Comparative analysis of the apo- and nsp10-bound structures explain the modulatory role of the co-factor protein and reveal the allosteric nsp14 control mechanism essential for drug discovery. Further, the flexibility of the N-terminal lid of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) nsp14 structure presented in this study rationalizes the recently proposed idea of nsp14/nsp10/nsp16 ternary complex.

Original languageEnglish
Pages (from-to)1050-1054.E2
Number of pages8
JournalStructure
Volume30
Issue number8
Early online date23 May 2022
DOIs
Publication statusPublished - 4 Aug 2022

Keywords

  • SARS-CoV-2
  • nsp14
  • nsp10
  • XRD
  • SAH
  • coronavirus
  • methylation
  • proof-reading
  • structure
  • methyltransferase

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