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PreprintCited by 82SARS-CoV-2 and COVID-19 ResearchAdvanced Electron Microscopy Techniques and ApplicationsEnzyme Structure and Function

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Structure of SARS-CoV-2 M protein in lipid nanodiscs

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Dolan, Kimberly A., Dutta, Mandira, Kern, David M., Kotecha, Abhay, Voth, Gregory A., Brohawn, Stephen G.·2022·eLife
DOI 10.1101/2022.06.12.495841PMC PMC9642992

Preprint — published as 10.7554/elife.81702 · Paper page

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Abstract

SARS-CoV-2 encodes four structural proteins incorporated into virions, spike (S), envelope (E), nucleocapsid (N), and membrane (M). M plays an essential role in viral assembly by organizing other structural proteins through physical interactions and directing them to sites of viral budding. As the most abundant protein in the viral envelope and a target of patient antibodies, M is a compelling target for vaccines and therapeutics. Still, the structure of M and molecular basis for its role in virion formation are unknown. Here, we present the cryo-EM structure of SARS-CoV-2 M in lipid nanodiscs to 3.5 Å resolution. M forms a 50 kDa homodimer that is structurally related to the SARS-CoV-2 ORF3a viroporin, suggesting a shared ancestral origin. Structural comparisons reveal how intersubunit gaps create a small, enclosed pocket in M and large open cavity in ORF3a, consistent with a structural role and ion channel activity, respectively. M displays a strikingly electropositive cytosolic surface that may be important for interactions with N, S, and viral RNA. Molecular dynamics simulations show a high degree of structural rigidity and support a role for M homodimers in scaffolding viral assembly. Together, these results provide insight into roles for M in coronavirus assembly and structure.

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Metadata

Authors
Dolan, K. A., Dutta, M., Kern, D. M., Kotecha, A., Voth, G. A., & Brohawn, S. G.
Affiliations
  • QB3 (US)
  • University of Chicago (US)
  • Thermo Fisher Scientific (Netherlands) (NL)
Corresponding author
Brohawn, Stephen G.
ORCID
Venue
eLife
Publisher
openRxiv
Published
2022-06-13
Volume
11
ISSN
2050-084X (ISSN-L)
DOI
10.1101/2022.06.12.495841
PMC
PMC9642992
OpenAlex
W4306879641
Cited by
82
References
1
Citations by year
2026: 17 · 2025: 18 · 2024: 20 · 2023: 21 · 2022: 6
FWCI
7.93
Type
journal article
Language
en
Open access
Licence
cc-by
Locations
  • eLife (publishedVersion, cc-by)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • eScholarship (California Digital Library) (submittedVersion, cc-by)
  • Knowledge@UChicago (University of Chicago) (submittedVersion, cc-by-nc-nd)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • University of Chicago (cc-by)
Funders
  • National Science Foundation (1818253, 2029092)
  • New York Stem Cell Foundation (R-N145)
  • George Mason University
  • University of Chicago
  • Colorado Department of Public Health and Environment
  • Thermo Fisher Scientific
  • Fast Grants
  • Mercatus Center, George Mason University
  • National Institute of General Medical Sciences (T32GM008295)
  • Division of Chemistry
Topics
  • Health Sciences › Medicine › Infectious Diseases › SARS-CoV-2 and COVID-19 Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Structural Biology › Advanced Electron Microscopy Techniques and Applications
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Structural Biology › Enzyme Structure and Function
Keywords
SARS-CoV-2, M protein, lipid nanodiscs, cryo-EM structure, homodimer, viral assembly, viral budding, ion channel activity, structural rigidity, molecular dynamics simulation
MeSH terms
COVID-19, SARS-CoV-2, Humans, Lipids, Nucleocapsid Proteins, Spike Glycoprotein, Coronavirus

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