Fig. 2

SARS-CoV-2 Membrane Fusion Pathway. (a) Structural diagrams of some key elements of S2 involved in membrane fusion. (b) Schematic summary of the essential steps in viral-host membrane fusion. Following the binding to ACE2, S protein must be cleaved by a protease, such as Transmembrane Serine Protease 2 (TMPRSS2), furin or cathepsin L to generate the S1 and S2 subunits, in order to release the S1 subunit; thus exposing the fusogenic core of S2 [109, 121, 242]. With its hydrophobic core exposed, S2 protein is now in a high-energy, pre-fusion, metastable state, fostered by the energetic imbalance induced by its uncovered core [150]. The S2 subunit can undergo a conformational change, extending heptad repeat 1 (HR1) and heptad repeat 2 (HR2) domains, and injecting its fusion peptide (FP) into the membrane of the host cell, forming the pre-hairpin intermediate. This pre-hairpin structure then folds back into a six helix bundle (6-HB), pulling apart the host membrane. Finally, the viral and host membranes fuse with one another, as HR1 and HR2 fold into a trimer of hairpins resulting in pore formation [152, 243]. The viral genome is then able to access the intracellular space of the host cell for transcription and replication. PDB codes for structures are referenced in Additional file 1: Table 5. Figure was created with  BioRender.com