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N-terminal domain of the S1 subunit of coronavirus Spike (S) proteins This family contains the N-terminal domain (NTD) of the S1 subunit of coronavirus (CoV) Spike (S) proteins from all four (A-D) lineages of betacoronaviruses, including three highly pathogenic human CoVs (HCoV) such as Middle East respiratory syndrome (MERS)-related CoV, Severe acute respiratory syndrome (SARS) CoV, and SARS-CoV-2, also known as a 2019 novel coronavirus (2019-nCoV) or COVID-19 virus. 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). Most CoVs, including SARS-CoV-2, SARS-CoV and MERS-CoV, use the C-domain to bind their receptors. However, some CoVs from the A lineage, such as mouse hepatitis virus (MHV) uses the NTD to bind its receptor, mouse carcinoembryonic antigen related cell adhesion molecule 1a (mCEACAM1a). Bovine CoV and HCoV-OC43, also from the A lineage, recognize a sugar moiety, 5-N-acetyl-9-O-acetylneuraminic acid (Neu5,9Ac2), on cell-surface glycoproteins or glycolipids; this binding is also through the S1 NTD. The S1 NTD has also been the target for neutralizing antibodies, including human antibody CDC2-A2, and murine antibodies G2 and 5F9, which target MERS-CoV NTD. In addition, the S1 NTD contributes to the Spike trimer interface. |
Jiyao W et al.(2023). "The conserved domain database in 2023.",