tetano
Editor, Senior Moderator
Nucleic Acids Res
. 2024 Mar 18:gkae165.
doi: 10.1093/nar/gkae165. Online ahead of print. Despite the odds: formation of the SARS-CoV-2 methylation complex
Alex Matsuda[SUP] 1 2 [/SUP], Jacek Plewka[SUP] 1 3 [/SUP], Michał Rawski[SUP] 4 [/SUP], André Mourão[SUP] 5 [/SUP], Weronika Zajko[SUP] 6 [/SUP], Till Siebenmorgen[SUP] 5 [/SUP], Leanid Kresik[SUP] 1 [/SUP], Kinga Lis[SUP] 1 7 [/SUP], Alisha N Jones[SUP] 5 8 [/SUP], Magdalena Pachota[SUP] 1 9 [/SUP], Abdulkarim Karim[SUP] 10 11 [/SUP], Kinga Hartman[SUP] 12 [/SUP], Shivlee Nirwal[SUP] 6 [/SUP], Ravi Sonani[SUP] 13 14 [/SUP], Yuliya Chykunova[SUP] 1 9 [/SUP], Igor Minia[SUP] 15 [/SUP], Paweł Mak[SUP] 16 [/SUP], Markus Landthaler[SUP] 15 [/SUP], Marcin Nowotny[SUP] 6 [/SUP], Grzegorz Dubin[SUP] 13 [/SUP], Michael Sattler[SUP] 5 8 [/SUP], Piotr Suder[SUP] 12 [/SUP], Grzegorz M Popowicz[SUP] 5 8 [/SUP], Krzysztof Pyrć[SUP] 1 [/SUP], Anna Czarna[SUP] 1 [/SUP]
Affiliations
Coronaviruses modify their single-stranded RNA genome with a methylated cap during replication to mimic the eukaryotic mRNAs. The capping process is initiated by several nonstructural proteins (nsp) encoded in the viral genome. The methylation is performed by two methyltransferases, nsp14 and nsp16, while nsp10 acts as a co-factor to both. Additionally, nsp14 carries an exonuclease domain which operates in the proofreading system during RNA replication of the viral genome. Both nsp14 and nsp16 were reported to independently bind nsp10, but the available structural information suggests that the concomitant interaction between these three proteins would be impossible due to steric clashes. Here, we show that nsp14, nsp10, and nsp16 can form a heterotrimer complex upon significant allosteric change. This interaction is expected to encourage the formation of mature capped viral mRNA, modulating nsp14's exonuclease activity, and protecting the viral RNA. Our findings show that nsp14 is amenable to allosteric regulation and may serve as a novel target for therapeutic approaches.
. 2024 Mar 18:gkae165.
doi: 10.1093/nar/gkae165. Online ahead of print. Despite the odds: formation of the SARS-CoV-2 methylation complex
Alex Matsuda[SUP] 1 2 [/SUP], Jacek Plewka[SUP] 1 3 [/SUP], Michał Rawski[SUP] 4 [/SUP], André Mourão[SUP] 5 [/SUP], Weronika Zajko[SUP] 6 [/SUP], Till Siebenmorgen[SUP] 5 [/SUP], Leanid Kresik[SUP] 1 [/SUP], Kinga Lis[SUP] 1 7 [/SUP], Alisha N Jones[SUP] 5 8 [/SUP], Magdalena Pachota[SUP] 1 9 [/SUP], Abdulkarim Karim[SUP] 10 11 [/SUP], Kinga Hartman[SUP] 12 [/SUP], Shivlee Nirwal[SUP] 6 [/SUP], Ravi Sonani[SUP] 13 14 [/SUP], Yuliya Chykunova[SUP] 1 9 [/SUP], Igor Minia[SUP] 15 [/SUP], Paweł Mak[SUP] 16 [/SUP], Markus Landthaler[SUP] 15 [/SUP], Marcin Nowotny[SUP] 6 [/SUP], Grzegorz Dubin[SUP] 13 [/SUP], Michael Sattler[SUP] 5 8 [/SUP], Piotr Suder[SUP] 12 [/SUP], Grzegorz M Popowicz[SUP] 5 8 [/SUP], Krzysztof Pyrć[SUP] 1 [/SUP], Anna Czarna[SUP] 1 [/SUP]
Affiliations
- PMID: 38499483
- DOI: 10.1093/nar/gkae165
Coronaviruses modify their single-stranded RNA genome with a methylated cap during replication to mimic the eukaryotic mRNAs. The capping process is initiated by several nonstructural proteins (nsp) encoded in the viral genome. The methylation is performed by two methyltransferases, nsp14 and nsp16, while nsp10 acts as a co-factor to both. Additionally, nsp14 carries an exonuclease domain which operates in the proofreading system during RNA replication of the viral genome. Both nsp14 and nsp16 were reported to independently bind nsp10, but the available structural information suggests that the concomitant interaction between these three proteins would be impossible due to steric clashes. Here, we show that nsp14, nsp10, and nsp16 can form a heterotrimer complex upon significant allosteric change. This interaction is expected to encourage the formation of mature capped viral mRNA, modulating nsp14's exonuclease activity, and protecting the viral RNA. Our findings show that nsp14 is amenable to allosteric regulation and may serve as a novel target for therapeutic approaches.