SARS-CoV-2 membrane protein biogenesis
Viral protein biogenesis underpins every viral life cycle stage, and elucidating these processes could reveal fundamental principles of virus-host interaction, and vulnerabilities amenable to therapeutic targeting. Here we apply biophysical, molecular, and cell biology techniques to investigate the insertion, folding, and oligomerization of the SARS-CoV-2 M protein. We describe the sequential co-translational insertion of the hydrophobic core, and demonstrate that the cytosolic C-terminal domain undergoes slower adoption of its tertiary structure. Additionally, we characterize how the transmembrane domain bundle facilitates M-protein oligomerization. Our results reveal a hydrophobic residue cluster that is essential for protein folding and co-translational dimerization. Additionally, we identify the cellular machinery responsible for targeting and inserting the M protein into the ER membrane, and chaperones and cofactors that may contribute to proper folding.
Authors
- Gunnar von Heijne (ORCID: https://orcid.org/0000-0002-4490-8569)
- Guy Pearson (ORCID: https://orcid.org/0000-0001-8623-9239)
- Luis Martínez‐Gil (ORCID: https://orcid.org/0000-0002-9076-7760)
- James C. Gumbart (ORCID: https://orcid.org/0000-0002-1510-7842)
- Ismael Mingarro (ORCID: https://orcid.org/0000-0002-1910-1229)
- Ane Metola (ORCID: https://orcid.org/0000-0002-2885-7634)
- Marina Rius-Salvador
- J. Mark Skehel
- Jeremy C. Carlton
- Josep Alonso-Romero
- Shiva Sedighian
- Manuel Mateo Sanchez-del Pino
- Anna Pavlova
- Juan Ortiz Mateu
- Maria Jesus Garcia-Murria
- Jose M Acosta-Caceres
Institutions
- Georgia Institute of Technology (US)
- Universitat de València (ES)
- Stockholm University (SE)
- King's College London (GB)
- Science for Life Laboratory (SE)
- The Francis Crick Institute (GB)
Publication Details
- Journal
- bioRxiv (Cold Spring Harbor Laboratory)
- Published
- 2026-01-20
- DOI
- https://doi.org/10.64898/2026.01.19.700281
- Primary Topic
- SARS-CoV-2 and COVID-19 Research
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Wellcome Trust
- Francis Crick Institute
- Ministerio de Ciencia, Innovación y Universidades
- Cancer Research UK
- European Commission
- Generalitat Valenciana
- Universitat de València
- Knut och Alice Wallenbergs Stiftelse
- Novo Nordisk
- Vetenskapsrådet
- Ministerio de Ciencia e Innovación
- Novo Nordisk Fonden
- National Institutes of Health
- Medical Research Council
- Agencia Estatal de Investigación