Despite myriad challenges, clinicians see room for progress.
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Contributed by James H. Hurley, November 12, 2020 (sent for review October 23, 2020; reviewed by Kevin D. Corbett and Robin E. Stanley)
Significance
The structure of the SARS-CoV-2 ORF8 protein reveals two novel intermolecular interfaces layered onto an ORF7 fold. One is mediated by a disulfide bond, the other is noncovalent, and both are novel with respect to SARS-CoV. The structural analysis here establishes a molecular framework for understanding the rapid evolution of ORF8, its contributions to COVID-19 pathogenesis, and the potential for its neutralization by antibodies.
Abstract
The molecular basis for the severity and rapid spread of the COVID-19 disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is largely unknown. ORF8 is a rapidly evolving accessory protein that has been proposed to interfere with immune responses. The crystal structure of SARS-CoV-2 ORF8 was determined at 2.04-Å resolution by X-ray crystallography. The structure reveals a ∼60-residue core similar to SARS-CoV-2 ORF7a, with the addition of two dimerization interfaces unique to SARS-CoV-2 ORF8. A covalent disulfide-linked dimer is formed through an N-terminal sequence specific to SARS-CoV-2, while a separate noncovalent interface is formed by another SARS-CoV-2−specific sequence, 73YIDI76. Together, the presence of these interfaces shows how SARS-CoV-2 ORF8 can form unique large-scale assemblies not possible for SARS-CoV, potentially mediating unique immune suppression and evasion activities.
Footnotes
↵1T.G.F. and C.Z.B. contributed equally to this work.
- ↵2To whom correspondence may be addressed. Email: jimhurley{at}berkeley.edu.
This contribution is part of the special series of Inaugural Articles by members of the National Academy of Sciences elected in 2020.
Author contributions: T.G.F., C.Z.B., and J.H.H. designed research; T.G.F., C.Z.B., R.M.H., M.A., and X.R. performed research; T.G.F., C.Z.B., R.M.H., and J.H.H. analyzed data; and T.G.F., C.Z.B., R.M.H., and J.H.H. wrote the paper.
Reviewers: K.D.C., University of California San Diego; and R.E.S., National Institute of Environmental Health Sciences.
The authors declare no competing interest.
This article contains supporting information online at https://www.pnas.org/lookup/suppl/doi:10.1073/pnas.2021785118/-/DCSupplemental.
Data Availability.
Coordinates have been deposited in the PDB, http://www.wwpdb.org (PDB ID code 7JTL). The expression construct has been made available at http://www.addgene.org.
- Copyright © 2021 the Author(s). Published by PNAS.
This open access article is distributed under Creative Commons Attribution License 4.0 (CC BY).
Structure of SARS-CoV-2 ORF8, a rapidly evolving immune evasion protein
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- Biological Sciences
- Biophysics and Computational Biology
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