Enric Pérez Parets (@enricpparets.bsky.social)

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 cotranslational 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. ### Competing Interest Statement The authors have declared no competing interest. Spanish Ministry of Science, Innovation and Universities Generalitat Valenciana European Union NextGenerationEU/PRTR University of Valencia Spanish Ministry of Science and Innovation Wellcome Trust Cancer Research UK UK Medical Research Council Knut and Alice Wallenberg Foundation Novo Nordisk Fund Swedish Research Council National Institutes of Health https://www.biorxiv.org/content/10.64898/2026.01.19.700281v1