Despite the odds: formation of the SARS-CoV-2 methylation complex (rapid access Covid-19 project)

Coronaviruses protect their ssRNA genome with a methylated cap. The methylation is performed by two methyltransferases, nsp14 and nsp16. Additionally, nsp14 carries an exonuclease domain, which operates in the proofreading system. nsp14 and nsp16 were reported to independently bind nsp10, but the available structural information suggests that the concomitant interaction between these three proteins should be impossible due to steric clashes. In our work (https://www.biorxiv.org/content/10.1101/2022.01.25.477673v1 ), we show that nsp14, nsp10, and nsp16 can form a ternary complex (MST, enzymatic assays, SAXS, TEM). This interaction is expected to encourage formation of mature capped viral mRNA, modulating the nsp14 exonuclease activity, and protecting the viral RNA. A high-resolution structure of the triplex would greatly improve the understanding of how the component proteins are undergoing the structural changes upon the ternary complex formation.