SD-1 and SD-2 subdomains, the S1/S2 cleavage region, and the S2 fusion subunit of the spike (S) glycoprotein from betacoronaviruses
This family contains the SD-1 and SD-2 subdomains of the S1 subunit C-terminal domain (C-domain), the S1/S2 cleavage region, and the S2 fusion subunit of the spike (S) glycoprotein from betacoronaviruses, including three highly pathogenic human coronaviruses (CoVs), Middle East respiratory syndrome coronavirus (MERS-CoV), Severe acute respiratory syndrome (SARS) coronavirus (SARS-CoV), and SARS coronavirus 2 (SARS-CoV-2), also known as a 2019 novel coronavirus (2019-nCoV). The CoV S protein is an envelope glycoprotein that plays a very important role in viral attachment, fusion, and entry into host cells, and serves as a major target for the development of neutralizing antibodies, inhibitors of viral entry, and vaccines. It is synthesized as a precursor protein that is cleaved into an N-terminal S1 subunit (~700 amino acids) and a C-terminal S2 subunit (~600 amino acids) that mediates attachment and membrane fusion, respectively. Three S1/S2 heterodimers assemble to form a trimer spike protruding from the viral envelope. The S1 subunit contains a receptor-binding domain (RBD), while the S2 subunit contains the coronavirus fusion machinery and is primarily alpha-helical. S1 contains two structurally independent domains, the N-terminal domain (NTD) and the C-domain. The S1 C-domain also contains two subdomains (SD-1 and SD-2), which connect the S1 and S2 subunits. Depending on the virus, either the NTD or the C-domain can serve as the receptor-binding domain (RBD). While the RBD of mouse hepatitis virus (MHV) is located at the NTD, most CoVs, including SARS-CoV-2, SARS-CoV and MERS-CoV use the C-domain to bind their receptors. The S2 subunit comprises the fusion peptide (FP), a second proteolytic site (S2'), followed by an internal fusion peptide (IFP) and two heptad-repeat domains (HR1 and HR2) preceding the transmembrane domain (TM). After binding of the S1 subunit RBD on the virion to its receptor on the target cell, the HR1 and HR2 domains interact with each other to form a six-helix bundle (6-HB) fusion core, bringing viral and cellular membranes into close proximity for fusion and infection. In order to catalyze the membrane fusion reaction, CoV S needs to be primed through cleavage at the S1/S2 and S2' sites. In the case of human-infecting coronaviruses such as SARS-CoV-2, HCoV-OC43, MERS-CoV, and HKU1, the spike protein contains an insertion of (R/K)-(2X)n-(R/K) (furin cleavage motif) at the S1/S2 site, which is absent in SARS-CoV and other SARS-related coronaviruses, as well as Rousettus bat coronavirus HKU9. The region modeled in this cd (SD-1 and SD-2, the S1/S2 cleavage region, and the S2 fusion subunit) plays an essential role in viral entry by initiating fusion of the viral and cellular membranes.