The Rough Endoplasmic Reticulum (RER), the SARS-CoV-2 S glycoprotein is produced as a 1273-amino-acid polyprotein precursor. At the N terminus of the unprocessed precursor is an Endoplasmic Reticulum (ER) signal sequence, which directs the S glycoprotein to the RER membrane and is degraded by cellular signal peptidases in the ER lumen. The S protein’s C terminus has a single stop-transfer, membrane-spanning motif that inhibits it from being fully released into the ER lumen and subsequent secretion from the infected cell. During synthesis, N-linked, high-mannose oligosaccharide side chains are added co-translationally. The S glycoprotein monomers trimerize shortly after synthesis, which may help in transport from the ER to the Golgi complex. Most high-mannose oligosaccharide side chains are changed to more complex forms in the Golgi complex, and O-linked oligosaccharide side chains are also added. The SARS-CoV-2 S glycoprotein, which contains numerous arginine residues not present in the closely related SARS-CoV, is proteolytically digested at the S1/S2 cleavage site in the transGolgi network by cellular furin or furin-like proteases. Surface component S1, which connects the virus to the host cell surface receptor, and transmembrane subunit S2, which facilitates the fusion of viral and host cell membranes, are produced via cleavage at the S1/S2 site. In a metastable prefusion state, noncovalent interactions keep the S1 and S2 subunits together.
