receptor-binding domain of the S1 subunit of the Spike (S) protein from human coronavirus HKU1 and related coronaviruses
This family contains the receptor-binding domain (RBD) of the S1 subunit of the spike (S) protein from human coronavirus (CoV) HKU1, human coronavirus OC43 (HCoV-OC43), mouse hepatitis virus (MHV), porcine hemagglutinating encephalomyelitis virus (HEV), and other related coronaviruses. HKU1 is a human betacoronavirus that causes mild yet prevalent respiratory disease. HCoV-OC43 is of zoonotic origin and is endemic in the human population, causing mild respiratory tract infections and possible severe complications or fatalities in young children, the elderly, and immunocompromised individuals. MHV is the most common viral pathogen in contemporary laboratory mouse colonies manifesting as a primary infection in the upper respiratory tract. Porcine HEV is associated with acute outbreaks of wasting and encephalitis in nursing piglets from pig farms. These viruses are related to the zoonotic SARS and MERS betacoronaviruses, which have high fatality rates and pandemic potential. The CoV S protein is an envelope glycoprotein that plays the most 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 a hydrophobic fusion peptide and two heptad repeat regions. S1 contains two structurally independent domains, the N-terminal domain (NTD) and the C-terminal domain (C-domain). Depending on the virus, either the NTD or the C-domain can serve as the receptor-binding domain (RBD). While the RBDs of MHV and HCoV-OC43 are located at the NTD, most CoVs use the C-domain to bind their receptors. Although a protein receptor has not yet been identified for HKU1, antibodies against the C-domain, but not those against the NTD, blocked HKU1 infection of cells, suggesting that the S1 C-domain is the primary HKU1 receptor-binding site. Due to the key role of the S protein RBD in viral attachment, it is the major target for antibody-mediated neutralization. This model corresponds to the S1 subunit C-domain that serves as the RBD for most CoVs.
Comment:This extended insertion is the receptor-binding motif (RBM) containing most of the contacting residues of SARS-CoV and SARS-CoV-2 for ACE2 (angiotensin-converting enzyme 2) binding.
Comment:The RBM includes all residues between the highlighted residues
Comment:Some members of this group, such as MHV and HCoV-OC43, have been shown to bind their receptors at the N-terminal domain of S1, which is not within this RBM.
Jiyao W et al.(2023). "The conserved domain database in 2023.",