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Chapter 5 : Coronavirus Replicative Proteins
Category: Viruses and Viral Pathogenesis
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Over the past few years, impressive progress into the functions and structures of coronavirus replicative proteins has been made. Nevertheless, our understanding of the molecular mechanisms that coronaviruses have evolved to synthesize, express, and maintain their unusually large RNA genomes is still far from being complete. Coronaviruses form one genus in the family Coronaviridae, which also contains the genus Torovirus and the tentative genus Bafinivirus. The family Coronaviridae has been grouped with the families Arteriviridae and Roniviridae in the virus order Nidovirales. Apart from similar genome structures and expression strategies, the phylogenetic relationship of corona-, toro-, bafini-, roni-, and arteriviruses is evident from the conserved array of replicase gene-encoded protein functions, which includes (i) a chymotrypsin-like protease (3CLpro/Mpro) that is flanked by membrane-spanning domains, (ii) a superfamily 1 RNA-dependent RNA polymerase (RdRp), (iii) a superfamily 1 helicase that has an amino-terminal Zn-binding domain (ZBD), and (iv) a uridylate-specific endoribonuclease (NendoU). Furthermore, coronaviruses encode 3’-to-5’ exoribonuclease (ExoN), putative ribose-2’-O-methyltransferase (MT), PLpro, and ADP-ribose 1’’-phosphatase (ADRP) activities, whereas putative cyclic nucleotide phosphodiesterase domains have been identified only in group 2a coronaviruses. A second, “noncanonical” polymerase activity has recently been identified in coronaviruses, which may act as a primase, thus further adding to the amazing complexity of the enzymology involved in coronavirus RNA synthesis. The functional domains and enzymatic activities associated with coronavirus nsp1 to nsp16 are summarized in this chapter.
Domain organizations of pp1a and pp1ab of representative viruses of coronavirus groups 1b, 2a, 2b, and 3 ( 46 ). Arrowheads indicate sites in pp1a and pp1ab that are cleaved by PL1pro and PL2pro (white and black, respectively) or the 3C-like main protease (gray). The proteolytic cleavage products (nsps) are numbered, and conserved domains are highlighted. Abbreviations: C/H, domains with conserved cysteine and histidine residues; Ac, acidic domain; A, ADRP; Y, Y domain; Rp, noncanonical RNA polymerase (potential primase); HEL, helicase; NeU, NendoU. Note that the IBV PL1 domain is proteolytically inactive.
Characteristics of coronavirus replicase gene-encoded nsps