PROSITE documentation PDOC51993

Coronavirus 3Ecto domain profile

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. SARS, SARS-CoV-2, BatCoV RaTG13 and Bat-SARS-like coronavirus (BATSL-CoVZXC21 and BAT-SL-CoVZC45) belong to the Sarbecovirus subgenus of βcoronavirus [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) to form the replication/ transcription complex (RTC). Among these, Nsp3 is the largest multi-domain protein produced by coronaviruses. This glycosylated, multi-domain, integral membrane protein plays many roles in the viral life cycle. It can act as a scaffold protein to interact with itself and to bind other viral Nsps or host proteins. In particular, Nsp3 is essential for RTC formation. Nsp3 comprises various domains of functional and structural importance for virus replication, the organization of which differs between CoV genera, due to duplication or absence of some domains. However, eight domains of Nsp3 exist in all known CoVs: the ubiquitin-like domain 1 (Ubl1) (see <PDOC51943>), the Glu-rich acidic domain (also called 'hypervariable region'), a macrodomain (also named 'X domain') (see <PDOC51154>), the ubiquitin-like domain 2 (Ubl2) (see <PDOC51943>), the papain-like protease 2 (PL2pro) (see <PDOC51124>), the Nsp3 ectodomain (3Ecto), as well as the Y domain which includes a widely-conserved initial domain (Y1), and an apparently coronavirus-specific carboxyl-terminal domain (CoV-Y). In addition, two transmembrane regions, TM1 and TM2, exist in all CoVs [1,2,3].

The CoV 3Ecto domain is glycosylated and predicted to be located on the lumenal side of the membrane. The transmembrane regions plus the 3Ecto are important for the PL2pro to process the Nsp3|4 cleavage site; a possible reason is that the transmembrane part could bring the PL2pro close to the cleavage site between the membrane-associated proteins Nsp3 and Nsp4. Asparagine (N)-linked glycosylation has been found in 3Ecto domains. It is unclear if the N-glycan modification affects the 3Ecto conformation or stability. Frequently, N-linked glycans serve as recognition points for partner molecules. It has been shown that interaction of the 3Ecto domain with the large lumenal loop of Nsp4 is essential for the endoplasmic reticulum (ER) rearrangements and double-membrane vesicles (DMVs) formation occurring in cells infected by SARS-CoV or mouse hepatitis virus (MHV) [1,2,3,4].

The CoV 3Ecto domain is predicted to mostly contain α-helices and to form two disulphide bonds between C1 and C4 as well as C2 and C3 [5].

The profile we developed covers the entire CoV 3Ecto domain.