Coronavirus spike protein S2 subunit (S2)

The coronavirus spike protein S2 subunit is the core component of the conserved coronavirus fusion machinery, facilitating the fusion of the viral envelope with the host cell membrane (Walls et al., 2020, Cell). While the S1 subunit mediates receptor binding and shows high variability, the S2 subunit is highly conserved across the Orthocoronavirinae subfamily, including SARS-CoV, SARS-CoV-2, and MERS-CoV (Xia et al., 2019, Science Advances). The fusion process is triggered by proteolytic cleavage and involves the transition of the S2 subunit from a metastable pre-fusion state to a stable post-fusion state. This transition is characterized by the formation of a six-helix bundle (6-HB) between the heptad repeat 1 (HR1) and heptad repeat 2 (HR2) domains (Huang et al., 2020, Acta Pharmacologica Sinica). This structural transition drives the insertion of the fusion peptide into the host membrane, bringing the viral and cellular membranes together for pore formation. Therapeutic agents targeting this machinery, such as the pan-coronavirus fusion inhibitor peptide EK1 and its lipid-modified derivative EK1C4, work by binding to the HR1 groove and preventing 6-HB formation (Xia et al., 2020, Cell Research). Because of its high conservation, the S2 subunit is a primary target for developing broad-spectrum antivirals and universal vaccines that could remain effective against emerging variants and novel zoonotic coronaviruses.

Other names

Spike protein S2 subunitConserved coronavirus fusion machineryS2 proteinFusion protein subunit

Inhibition of the six-helix bundle (6-HB) formation by binding to the heptad repeat 1 (HR1) domain, thereby preventing the fusion of the viral envelope with the host cell membrane.