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

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...

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Autores principales: Czarna, Anna, Plewka, Jacek, Kresik, Leanid, Matsuda, Alex, Karim, Abdulkarim, Robinson, Colin, O’Byrne, Sean, Cunningham, Fraser, Georgiou, Irene, Wilk, Piotr, Pachota, Magdalena, Popowicz, Grzegorz, Wyatt, Paul Graham, Dubin, Grzegorz, Pyrć, Krzysztof
Formato: Online Artículo Texto
Lenguaje:English
Publicado: The Author(s). Published by Elsevier Ltd. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9125827/
https://www.ncbi.nlm.nih.gov/pubmed/35609600
http://dx.doi.org/10.1016/j.str.2022.04.014
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author Czarna, Anna
Plewka, Jacek
Kresik, Leanid
Matsuda, Alex
Karim, Abdulkarim
Robinson, Colin
O’Byrne, Sean
Cunningham, Fraser
Georgiou, Irene
Wilk, Piotr
Pachota, Magdalena
Popowicz, Grzegorz
Wyatt, Paul Graham
Dubin, Grzegorz
Pyrć, Krzysztof
author_facet Czarna, Anna
Plewka, Jacek
Kresik, Leanid
Matsuda, Alex
Karim, Abdulkarim
Robinson, Colin
O’Byrne, Sean
Cunningham, Fraser
Georgiou, Irene
Wilk, Piotr
Pachota, Magdalena
Popowicz, Grzegorz
Wyatt, Paul Graham
Dubin, Grzegorz
Pyrć, Krzysztof
author_sort Czarna, Anna
collection PubMed
description 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.
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spelling pubmed-91258272022-05-23 Refolding of lid subdomain of SARS-CoV-2 nsp14 upon nsp10 interaction releases exonuclease activity Czarna, Anna Plewka, Jacek Kresik, Leanid Matsuda, Alex Karim, Abdulkarim Robinson, Colin O’Byrne, Sean Cunningham, Fraser Georgiou, Irene Wilk, Piotr Pachota, Magdalena Popowicz, Grzegorz Wyatt, Paul Graham Dubin, Grzegorz Pyrć, Krzysztof Structure Article 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. The Author(s). Published by Elsevier Ltd. 2022-08-04 2022-05-23 /pmc/articles/PMC9125827/ /pubmed/35609600 http://dx.doi.org/10.1016/j.str.2022.04.014 Text en © 2022 The Author(s) Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active.
spellingShingle Article
Czarna, Anna
Plewka, Jacek
Kresik, Leanid
Matsuda, Alex
Karim, Abdulkarim
Robinson, Colin
O’Byrne, Sean
Cunningham, Fraser
Georgiou, Irene
Wilk, Piotr
Pachota, Magdalena
Popowicz, Grzegorz
Wyatt, Paul Graham
Dubin, Grzegorz
Pyrć, Krzysztof
Refolding of lid subdomain of SARS-CoV-2 nsp14 upon nsp10 interaction releases exonuclease activity
title Refolding of lid subdomain of SARS-CoV-2 nsp14 upon nsp10 interaction releases exonuclease activity
title_full Refolding of lid subdomain of SARS-CoV-2 nsp14 upon nsp10 interaction releases exonuclease activity
title_fullStr Refolding of lid subdomain of SARS-CoV-2 nsp14 upon nsp10 interaction releases exonuclease activity
title_full_unstemmed Refolding of lid subdomain of SARS-CoV-2 nsp14 upon nsp10 interaction releases exonuclease activity
title_short Refolding of lid subdomain of SARS-CoV-2 nsp14 upon nsp10 interaction releases exonuclease activity
title_sort refolding of lid subdomain of sars-cov-2 nsp14 upon nsp10 interaction releases exonuclease activity
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9125827/
https://www.ncbi.nlm.nih.gov/pubmed/35609600
http://dx.doi.org/10.1016/j.str.2022.04.014
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