PROSITE documentation PDOC51992

Coronavirus (CoV) Nsp3 Y 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) consisting of three distinct subdomains named Y2, Y3 and Y4. In addition, two transmembrane regions, TM1 and TM2, exist in all CoVs [1,2,3,4].

The Y domains including Y1 and CoV-Y may form higher-order oligomeric complexes and play a role in pore formation in double-membrane vesicles (DMVs) that serve as the central hubs for viral RNA replication. Specific membrane binding might be a conserved activity of the Y domain [4].

The Y1 domain is predicted to contain two adjacent zinc finger (ZF)-like motifs. The first IF motif (ZF1) adopts a HCCC-type TAZ2 domain-like zinc-binding site. The second ZF motif (ZF2) harbors a CHCC-type zinc-binding site. The CoV-Y domain has a twisted structure resembling a letter V. The protein is organized into three distinct subdomains (Y2, Y3 and Y4) with a deep cleft in the middle (see <PDB:8F2E>). The N-terminal Y2 subdomain is dominated by six β strands arranged into two nearly orthogonal β sheets to form a β sandwich like structure packed across a hydrophobic core. An α helix stacks on the exposed side of the parallel sheet, whereas three short 3(10) helices surround the open side of the β sandwich. The middle Y3 subdomain adopts a compact α helical fold composed of a three-helix bundle packing against the 4th helix. All four helices of the Y3 subdomain are largely amphipathic, with polar and charged residues on the outside and nonpolar side chains buried inside. The C-terminal Y4 subdomain consists of a α/β fold with two three-stranded β sheets in the center flanked by three α helices and a 3(10) helix (see <PDB:7RQG>) [4].

The profile we developed covers the entire CoV Nsp3 Y domain.