Direct lipid interactions control SARS-CoV-2 M protein conformational dynamics and virus assembly
- Mandira Dutta
- Kimberly A. Dolan
- Souad Amiar
- Elijah J. Bass
- Rokaia Sultana
- Sean M. Braet
- Karen J. Cárdenas-Martínez
- Devika Sirohi
- Ian K. Hicklin
- Richard J. Kuhn
- Ganesh S. Anand
- Gregory A. Voth
- Stephen G. Brohawn
- Robert V. Stahelin
2026-07-23
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, interaction with other structural proteins, 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 colocalization with Spike and E, and reduces virus-like particle formation and 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.