PROSITE documentation PDOC51922

Betacoronavirus spike (S) glycoprotein S1 subunit N-terminal (NTD) domain profile

Coronaviruses (CoVs) [E1] primarily cause respiratory and enteric diseases in humans, animals, and birds, and some CoVs also cause systemic diseases, including hepatitis or neurological diseases. Phylogenetically, CoVs are divided into four genera, called the α-, β-, γ-, and delta-CoVs. Of these, βcoronaviruses (βCoVs) [E1] have attracted attention worldwide because of their pathogenic capacity and potential to cause a global pandemic of human infections and the widespread existence of an enormous number of species in bats. Three highly pathogenic human coronaviruses (CoVs) have been identified so far, including Middle East respiratory syndrome coronavirus (MERS-CoV), severe acute respiratory syndrome (SARS) coronavirus (SARS-CoV), and a 2019 novel coronavirus SARS-CoV-2 [1,2,3,4].

A coronavirus contains four structural proteins, including spike (S), envelope (E), membrane (M), and nucleocapsid (N) proteins. Among them, the S protein, which is located on the envelope surface of the virion, functions to mediate receptor recognition and membrane fusion and is therefore a key factor determining the virus tropism for a specific species. In most cases, coronaviral S will be further cleaved into S1 and S2 subunits, and the receptor binding capacity is allocated to the S1 subunit. The receptor binding domain (RBD) of βCoV that directly engages the receptor is commonly located in the C-terminal half of S1 [C-terminal domain (CTD)] such as in SARS-CoV, SARS-CoV-2, MERS-CoV,and BatCoV HKU4, though in rare cases such as with mouse hepatitis virus (MHV), the RBD region was identified in the S1 N-terminal domain (NTD), which mainly recognizes sugar receptors [1,2,3,4].

The βCoV NTDs contain a conserved β-sandwich core, but exhibit variant folds in the peripheral elements located in the top-ceiling region and on the lateral side (see <PDB:6JHY>). The core sandwich comprises in total sixteen anti-parallel β-strands, assembling into three (upper, middle, and lower) β-sheet layers. While showing different compositions and structures, the peripheral elements are topologically equivalent β-sandwich-core insertions, highlighting a divergent evolution process for βCoVs to form different lineages [2].

The profile we developed covers the entire βCoV S1-NTD domain.