NSP3, first ubiquitin-like (Ubl) domain, coronavirus (NSP3_Ubl1_dom_CoV)
Type: Domain

Non-structural protein NSP3 is a multi-domain protein, the largest product of coronavirus ORF1a which encodes the poyprotein 1a/1ab (pp1a/1ab). NSP3 is released from pp1a/1ab by the papain-like protease domain(s), which is (are) part of NSP3 itself. NSP3 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 the formation of the the replication/ transcription complex (RTC). The RTC associates with host ER membranes producing convoluted membranes and double-membrane vesicles. It is also involved in post-translational modifications of host proteins to antagonise its innate immune response .

NSP3 comprises up to 16 different domains and regions, their organisation differs between coronaviruses (CoV). However, eight domains and two transmembrane regions are conserved in all known CoVs: the ubiquitin-like domain 1 (Ubl1), the Glu-rich acidic domain (hypervariable region), a macrodomain (X domain), the ubiquitin-like domain 2 (Ubl2), the papain-like protease 2 (PL2pro, depending on the CoV there are one or two PLpro), the NSP3 ectodomain (3Ecto, also called "zinc-finger domain"), as well as the domains Y1, Y2 and Y3 of unknown functions. The Y1 domain is conserved in all viruses of the order Nidovirales, while Y2 and Y3 are conserved in all coronaviruses. The three domains from the Y region (Y1 to Y3) are located at the cytosolic side of the ER. The level of their conservation is close to that for the enzymatic domains of Nsp3 and exceeds nonenzymatic ones. From the consistently high conservation of Y1, Y2, and Y3, it has been hypothesize that Y1 to Y3 may form a single functional unit with a conserved enzymatic function .

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 . Two ubiquitin-like domains, Ubl1 and Ubl2 (Nsp3a and the N-terminal domain of Nsp3d), exist within Nsp3 of all CoVs. The known functional roles of Nsp3a Ubl in CoVs are related to single-stranded (ssRNA) binding and interacting with the nucleocapsid (N) protein . Nsp3d Ubl is immediately adjacent to the N terminus of the PLpro (or PL2Pro) domain in CoV polyproteins, and it may play a critical role in protease regulation and stability as well as in viral infection . In addition to the four β-strands and two α-helices that are common to ubiquitin-like folds, the Nsp3a Ubl domain contains two short helices . The Nsp3d Ubl domain comprises five β-strands, one α-helix, and one 3(10)-helix . This entry represents a domain covering the entire CoV Nsp3a and Nsp3d first Ubl domain. NSP3a interacts with numerous other proteins involved in replication and transcription and may serve as a scaffolding protein for these processes. The Ubl1 domain interacts with N protein to co-localise genomic RNA with the nascent replicase-transcriptase complex at the earliest stages of infection, essential for the virus . This Ubl1 domain may bind ssRNA with AUA patterns. The C-terminal Glu-rich subdomain is best described as a flexible tail attached to the globular UB1 subdomain .