CryoEM and AI reveal a structure of SARS-CoV-2 Nsp2, a multifunctional protein involved in key host processes.
By
Meghna Gupta,
Caleigh M. Azumaya,
Michelle Moritz,
Sergei Pourmal,
Amy Diallo,
Gregory E. Merz,
Gwendolyn M. Jang,
Mehdi Bouhaddou,
Andrea Fossati,
Axel F Brilot,
Devan Diwanji,
Evelyn Hernandez,
Nadia Herrera,
Huong T Kratochvil,
Victor L. Lam,
Fei Li,
Yang Li,
Henry C. Nguyen,
Carlos Nowotny,
Tristan W. Owens,
Jessica K Peters,
Alexandrea N. Rizo,
Ursula Schulze-Gahmen,
Amber Smith,
Iris D. Young,
Zanlin Yu,
Daniel Asarnow,
Christian B. Billesbølle,
Melody G. Campbell,
Jen Chen,
Kuei-Ho Chen,
Un Seng Chio,
Miles Sasha Dickinson,
Loan Doan,
Mingliang Jin,
Kate Kim,
Junrui Li,
Yen-Li Li,
Edmond Linossi,
Yanxin Liu,
Megan Lo,
Jocelyne Lopez,
Kyle E Lopez,
Adamo Mancino,
Frank Russell Moss,
Michael Paul,
Komal Ishwar Pawar,
Adrian Pelin,
Thomas H. Pospiech,
Cristina Puchades,
Soumya Govinda Remesh,
Maliheh Safari,
Kaitlin Schaefer,
Ming Sun,
Mariano C. Tabios,
Aye C. Thwin,
Erron W. Titus,
Raphael Trenker,
Eric Tse,
Tsz Kin Martin Tsui,
Feng Wang,
Kaihua Zhang,
Yang Zhang,
Jianhua Zhao,
Fengbo Zhou,
Yuan Zhou,
Lorena Zuliani-Alvarez,
David A Agard,
Yifan Cheng,
James S. Fraser,
Natalia Jura,
Tanja Kortemme,
Aashish Manglik,
Daniel R Southworth,
Robert M. Stroud,
Danielle L Swaney,
Nevan J Krogan,
Adam Frost,
Oren S Rosenberg,
Kliment A Verba
Posted 12 May 2021
bioRxiv DOI: 10.1101/2021.05.10.443524
The SARS-CoV-2 protein Nsp2 has been implicated in a wide range of viral processes, but its exact functions, and the structural basis of those functions, remain unknown. Here, we report an atomic model for full-length Nsp2 obtained by combining cryo-electron microscopy with deep learning-based structure prediction from AlphaFold2. The resulting structure reveals a highly-conserved zinc ion-binding site, suggesting a role for Nsp2 in RNA binding. Mapping emerging mutations from variants of SARS-CoV-2 on the resulting structure shows potential host-Nsp2 interaction regions. Using structural analysis together with affinity tagged purification mass spectrometry experiments, we identify Nsp2 mutants that are unable to interact with the actin-nucleation-promoting WASH protein complex or with GIGYF2, an inhibitor of translation initiation and modulator of ribosome-associated quality control. Our work suggests a potential role of Nsp2 in linking viral transcription within the viral replication-transcription complexes (RTC) to the translation initiation of the viral message. Collectively, the structure reported here, combined with mutant interaction mapping, provides a foundation for functional studies of this evolutionary conserved coronavirus protein and may assist future drug design.
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