Molecular biology of severe acute respiratory syndrome coronavirus

Abstract

The worldwide epidemic of severe acute respiratory syndrome (SARS) in 2003 was caused by a novel coronavirus called SARS-CoV. Coronaviruses and their closest relatives possess extremely large plus-strand RNA genomes and employ unique mechanisms and enzymes in RNA synthesis that separate them from all other RNA viruses. The SARS epidemic prompted a variety of studies on multiple aspects of the coronavirus replication cycle, yielding both rapid identification of the entry mechanisms of SARS-CoV into host cells and valuable structural and functional information on SARS-CoV proteins. These recent advances in coronavirus research have important implications for the development of anti-SARS drugs and vaccines.

Figure 1

Genome organization and RNA synthesis of SARS-CoV. The putative functional ORFs in the genome of SARS-CoV are indicated. The 14 ORFs are expressed from the genome RNA (mRNA 1) and a nested set of sg mRNAs (mRNAs 2–9) that all have a common leader sequence derived from the 5′ end of the genome. The complement of this leader sequence (‘antileader’) is fused to the 3′ ends of nascent minus-strands by discontinuous RNA synthesis, which involves transcription-regulating sequences, the positions of which in the genome RNA are indicated here (see main text for details). The key functions that are required for the replication of the viral genome RNA and the synthesis of sg RNAs are encoded by the SARS-CoV replicase gene, comprising ORFs 1a and 1b. Expression of ORF1b sequences requires a programmed ribosomal frameshift into the –1 reading frame during translation of the genome RNA, which occurs just upstream of the ORF1a translation stop codon.

Figure 2

Overview of the domain organization and proteolytic processing of SARS-CoV replicase polyproteins, pp1a (486 kDa) and pp1ab (790 kDa). The processing end-products of pp1a are designated nonstructural proteins (nsp) 1 to nsp11 and those of pp1ab are designated nsp1 to nsp10 and nsp12 to nsp16. Cleavage sites that are predicted to be processed by the viral main protease, 3CL^pro, are indicated by grey arrowheads, and sites that are processed by the papain-like protease, PL2^pro, are indicated by black arrowheads. For further details on SARS-CoV replicative proteins, see Table 1. ADRP, ADP-ribose 1″-phosphatase; PL2^pro, papain-like protease 2; 3CL^pro, 3C-like main protease; RdRp, RNA-dependent RNA polymerase; TM1, TM2, TM3, transmembrane domains 1, 2 and 3; C/H, domains containing conserved Cys and His residues.