Torsional Twist of the SARS-CoV and SARS-CoV-2 SUD-N and SUD-M domains

Rosas-Lemus, M.; Minasov, G.; Brunzelle, J. S.; Taha, T. Y.; Lemak, S.; Yin, S.; Shuvalova, L.; Rosecrans, J.; Khanna, K.; Seifert, H. S.; Savchenko, A.; Stogios, P. J.; Ott, M.; Satchell, K. J.

doi:10.1101/2024.08.13.607777

bioRxiv · 10.1101/2024.08.13.607777

Torsional Twist of the SARS-CoV and SARS-CoV-2 SUD-N and SUD-M domains

Rosas-Lemus, M.·Minasov, G.·Brunzelle, J. S.·Taha, T. Y.·Lemak, S.·Yin, S.·Shuvalova, L.·Rosecrans, J.·Khanna, K.·Seifert, H. S.·Savchenko, A.·Stogios, P. J.·Ott, M.·Satchell, K. J.

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Abstract

Coronavirus non-structural protein 3 (nsp3) forms hexameric crowns of pores in the double membrane vacuole that houses the replication-transcription complex. Nsp3 in SARS-like viruses has three unique domains absent in other coronavirus nsp3 proteins. Two of these, SUD-N (Macrodomain 2) and SUD-M (Macrodomain 3), form two lobes connected by a peptide linker and an interdomain disulfide bridge. We resolve the first complete x-ray structure of SARS-CoV SUD-N/M as well as a mutant variant of SARS-CoV-2 SUD-N/M modified to restore cysteines for interdomain disulfide bond naturally lost by evolution. Comparative analysis of all structures revealed SUD-N and SUD-M are not rigidly associated, but rather, have significant rotational flexibility. Phylogenetic analysis supports that the disulfide bond cysteines are also absent in pangolin-SARS and closely related viruses, consistent with pangolins being the presumed intermediate host in the emergence of SARS-CoV-2. The absence of these cysteines does not impact viral replication or protein translation.

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Rosas-Lemus, M., Minasov, G., Brunzelle, J. S., Taha, T. Y., Lemak, S., Yin, S., Shuvalova, L., Rosecrans, J., Khanna, K., Seifert, H. S., Savchenko, A., Stogios, P. J., Ott, M., Satchell, K. J.. 2024-08-14. Torsional Twist of the SARS-CoV and SARS-CoV-2 SUD-N and SUD-M domains. https://doi.org/10.1101/2024.08.13.607777

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