CryoEM and AI reveal a structure of SARS-CoV-2 Nsp2, a multifunctional protein involved in key host processes.
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 M. Smith; Iris D. Young; Zanlin Yu; Daniel Asarnow; Christian Billesbolle; 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 R. Moss III; Michael D. Paul; Komal Ishwar Pawar; Adrian Pelin; Thomas H. Pospiech Jr.; 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.
Preprint
en Inglés
| PREPRINT-BIORXIV | ID: ppbiorxiv-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.
Texto completo
Documentos relacionados