PROSITE documentation PDOC51962

Coronavirus (CoV) Nsp1 globular and Betacoronavirus (BetaCoV) Nsp1 C-terminal domains profiles

Coronaviruses (CoVs) are enveloped positive-strand RNA viruses that infect many species, including humans, other mammals, and birds. After infection, the host may develop respiratory, bowel, liver, and neurological diseases. Coronaviruses are divided into four genera: αcoronavirus, βcoronavirus, γcoronavirus, and Deltacoronavirus. The ideal hosts of αCoV and βCoV are mammals, and γCoV primarily infects birds, while DeltaCoV has been identified in both mammals and birds. SARS, SARS-CoV-2, BatCoV RaTG13 and Bat-SARS-like coronavirus (BATSL-CoVZXC21 and BAT-SL-CoVZC45) belong to the Sarbecovirus subgenus of βCoV [E1].

The CoV replicase gene encodes two overlapping polyproteins, termed pp1a and pp1ab, which mediate viral replication and transcription. The polypeptides pp1a and pp1ab are processed by the action of a main protease (Nsp5) (see <PDOC51442>) and of one or two papain-like proteases (PLpro) (see <PDOC51124>) found in Nsp3 into non-structural proteins (Nsps) that predominantly play a role in replication and transcription. Although the CoV genome is highly conserved within genera, Nsp1, which is located at the N terminus of the replicase polyprotein pp1a, is responsible for the majority of variation. Nsp1 is a critical virulence factor of coronaviruses and plays key roles in suppressing host gene expression, which facilitates viral replication and immune evasion. Nsp1 is a characteristic feature of αCoVs and βCoVs, which exhibits both functional conservation and mechanistic diversity in inhibiting host gene expression and antiviral responses. Only αCoVs and βCoVs encode Nsp1, whereas DeltaCoVs and γCoVs lack this protein. The sizes of αCoV Nsp1 and βCoV Nsp1 differ; the αCoVs encode Nsp1 proteins of ~9 kDa, which are substantially smaller than the ~20-kDa Nsp1 proteins of βCoVs. Although the sequence homologies among CoV Nsp1 proteins are low, the core structures share a relatively conserved domain. This high structural similarity may explain why CoV Nsp1 has the conserved biological function of inhibiting host gene expression. However, the critical region of βCoV Nsp1 required to inhibit protein synthesis is different from that of αCoV Nsp1 [1,2,3,4]. In addition to the globular domain, βCoV Nsp1s contain a C-terminal domain. The Sarbecovirus Nsp1 C-terminal domain binds to the mRNA channel of the 40S ribosome, where it interferes with mRNA binding and inhibits host protein translation. The 5' UTR of Sarbecovirus mRNA removes this inhibition by binding to the Nsp1 globular domain. This inhibition mechanism may be unique to Sarbecoviruses, because the C-terminal region of Nsp1 is shorter in αCoVs and is not highly conserved amongst other βCoVs, including MERS-CoV [5,6,7,8].

The CoV Nsp1 globular domain displays a six-stranded β-barrel fold with a long α helix on the rim of the barrel (see <PDB:3ZBD>). The core of the β-barrel is highly hydrophobic [1,2,4]. The βCoV Nsp1 C-terminal domain comprises two α helices and two short loops (see <PDB:7JQC>) [5,6,7].

The profiles we developed cover respectively the entire CoV Nsp1 globular and βCoV Nsp1 C-terminal domains.