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Peer-reviewedCC BYNature Communications

Direct lipid interactions control SARS-CoV-2 M protein conformational dynamics and virus assembly

  • Mandira Dutta1,2
  • Kimberly A. Dolan3,4
  • Souad Amiar5,6,7
  • Elijah J. Bass5,6,7
  • Rokaia Sultana5,6,7
  • Sean M. Braet8,9
  • Karen Johanna Cárdenas-Martínez5,6,10
  • Devika Sirohi11,6,7
  • Ian K. Hicklin3
  • Richard J. Kuhn11,6
  • Ganesh S. Anand8
  • Gregory A. Voth12,13
2 more authors
  • Stephen Graf Brohawn14
  • Robert Virgil Stahelin15,16
16 affiliations
  1. 1Department of Chemistry, The University of Chicago, Chicago, IL, USA
  2. 2The University of Chicago
  3. 3Department of Molecular & Cell Biology, Department of Neuroscience, California Institute for Quantitative Biology (QB3), Biophysics Graduate Program, University of California Berkeley, Berkeley, CA, USA
  4. 4University of California, Berkeley
  5. 5Borch Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, West Lafayette, IN, USA
  6. 6Purdue Institute of Inflammation, Immunology and Infectious Disease, Purdue University, West Lafayette, IN, USA
  7. 7Purdue University
  8. 8Department of Chemistry, Pennsylvania State University, University Park, PA, USA
  9. 9University of Chicago
  10. 10University of California Berkeley
  11. 11Department of Biological Sciences, Purdue University, West Lafayette, IN, USA
  12. 12Chicago Center for Theoretical Chemistry, Institute for Biophysical Dynamics, and James Franck Institute, The University of Chicago, Chicago, IL, USA. [email protected]
  13. 13Department of Chemistry, The University of Chicago, Chicago, IL, USA. [email protected]
  14. 14Department of Molecular & Cell Biology, Department of Neuroscience, California Institute for Quantitative Biology (QB3), Biophysics Graduate Program, University of California Berkeley, Berkeley, CA, USA. [email protected]
  15. 15Borch Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, West Lafayette, IN, USA. [email protected]
  16. 16Purdue Institute of Inflammation, Immunology and Infectious Disease, Purdue University, West Lafayette, IN, USA. [email protected]
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Abstract

M is the most abundant structural membrane protein in coronaviruses and is essential for the formation of infectious virus particles. SARS-CoV-2 M adopts two conformations, M short and M long , and regulated transition between states is hypothesized to coordinate viral assembly and budding. However, the factors that regulate M conformation and roles for each state are unknown. Here, we discover a direct M-sphingolipid interaction that controls M conformational dynamics and virus assembly. We show M binds Golgi-enriched anionic lipids including ceramide-1-phosphate (C1P). Molecular dynamics simulations show C1P interaction promotes a long to short transition and energetically stabilizes M short . Cryo-EM structures show C1P specifically binds M short at a conserved site bridging transmembrane and cytoplasmic regions. Disrupting M short -C1P interaction alters M subcellular localization, reduces interaction with Spike and E, and impairs subsequent virus-like particle cell entry. Together, these results show endogenous signaling lipids regulate M structure and support a model in which M short is stabilized in the early endomembrane system to organize other structural proteins prior to viral budding.

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Cite

BibTeXRIS
BibTeX
@article{dutta2026direct,
  title = {{Direct lipid interactions control SARS-CoV-2 M protein conformational dynamics and virus assembly}},
  author = {Mandira Dutta and Kimberly A. Dolan and Souad Amiar and Elijah J. Bass and Rokaia Sultana and Sean M. Braet and Karen Johanna Cárdenas-Martínez and Devika Sirohi and Ian K. Hicklin and Richard J. Kuhn and Ganesh S. Anand and Gregory A. Voth and Stephen Graf Brohawn and Robert Virgil Stahelin},
  journal = {Nature Communications},
  year = {2026},
  month = jul,
  doi = {10.1038/s41467-026-75229-9},
  url = {https://doi.org/10.1038/s41467-026-75229-9},
  note = {CC BY},
}
RIS
TY  - JOUR
TI  - Direct lipid interactions control SARS-CoV-2 M protein conformational dynamics and virus assembly
AU  - Mandira Dutta
AU  - Kimberly A. Dolan
AU  - Souad Amiar
AU  - Elijah J. Bass
AU  - Rokaia Sultana
AU  - Sean M. Braet
AU  - Karen Johanna Cárdenas-Martínez
AU  - Devika Sirohi
AU  - Ian K. Hicklin
AU  - Richard J. Kuhn
AU  - Ganesh S. Anand
AU  - Gregory A. Voth
AU  - Stephen Graf Brohawn
AU  - Robert Virgil Stahelin
PY  - 2026
DA  - 2026/07/23
JO  - Nature Communications
DO  - 10.1038/s41467-026-75229-9
UR  - https://doi.org/10.1038/s41467-026-75229-9
AB  - M is the most abundant structural membrane protein in coronaviruses and is essential for the formation of infectious virus particles. SARS-CoV-2 M adopts two conformations, M short and M long , and regulated transition between states is hypothesized to coordinate viral assembly and budding. However, the factors that regulate M conformation and roles for each state are unknown. Here, we discover a direct M-sphingolipid interaction that controls M conformational dynamics and virus assembly. We show M binds Golgi-enriched anionic lipids including ceramide-1-phosphate (C1P). Molecular dynamics simulations show C1P interaction promotes a long to short transition and energetically stabilizes M short . Cryo-EM structures show C1P specifically binds M short at a conserved site bridging transmembrane and cytoplasmic regions. Disrupting M short -C1P interaction alters M subcellular localization, reduces interaction with Spike and E, and impairs subsequent virus-like particle cell entry. Together, these results show endogenous signaling lipids regulate M structure and support a model in which M short is stabilized in the early endomembrane system to organize other structural proteins prior to viral budding.
SN  - 2041-1723
ER  -