Publication date: Jul 23, 2026
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 and M, 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. Cryo-EM structures show C1P specifically binds M at a conserved site bridging transmembrane and cytoplasmic regions. Disrupting M-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 is stabilized in the early endomembrane system to organize other structural proteins prior to viral budding.
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Semantics
| Type | Source | Name |
|---|---|---|
| pathway | REACTOME | Budding |
| drug | DRUGBANK | Phosphate ion |
| disease | MESH | fac |
| disease | MESH | infection |
| disease | MESH | hepatitis |
| drug | DRUGBANK | Cholesterol |
| disease | MESH | Inflammation |
| disease | MESH | Infectious Disease |
| pathway | REACTOME | Infectious disease |
| disease | MESH | Park |
| pathway | REACTOME | Release |
| drug | DRUGBANK | Sphingosine |
| drug | DRUGBANK | Coenzyme M |
| drug | DRUGBANK | Sulfatide |
| drug | DRUGBANK | Dimethyl sulfoxide |
| drug | DRUGBANK | Proline |
| drug | DRUGBANK | Trestolone |
| drug | DRUGBANK | Potassium Chloride |
| drug | DRUGBANK | L-Arginine |
| drug | DRUGBANK | Histidine |
| drug | DRUGBANK | L-Alanine |
| disease | MESH | dis |
| drug | DRUGBANK | Flunarizine |
| disease | MESH | gra |
| disease | MESH | ***ns |
| pathway | KEGG | Virion |
| drug | DRUGBANK | Amitriptyline |
| disease | MESH | SARS CoV 2 infection |
| drug | DRUGBANK | Hexadecanal |
| drug | DRUGBANK | Inositol |
| drug | DRUGBANK | Phosphatidyl serine |
| drug | DRUGBANK | Methylergometrine |
| drug | DRUGBANK | Isoxaflutole |