ORF1ab

programmed ribosomal frameshift that allows the ribosome to continue translating past the stop codon at the end of ORF1a, in a -1 reading frame. The resulting polyproteins are known as pp1a and pp1ab.^[1][2][3][4]

kb for coronaviruses^[1]), but ORF1ab is translated directly from the genomic RNA.^[5] ORF1ab sequences have been observed in noncanonical subgenomic RNAs, though their functional significance is unclear.^[5]

RNA secondary structure.^[1] This has been measured at between 20-50% efficiency for murine coronavirus,^[6] or 45-70% in SARS-CoV-2^[7] yielding a stoichiometry of roughly 1.5 to 2 times as much pp1a as pp1ab protein expressed.^[2]

polyproteins pp1a and pp1ab contain about 13 to 17 nonstructural proteins.^[3] They undergo auto-proteolysis to release the nonstructural proteins due to the actions of internal cysteine protease domains.^[1][2][3]

3CL protease (also known as the main protease, nsp5) performs the remaining cleavages of nsp5 through the polyprotein C-terminus.^[1][2] Proteins nsp12-16, the C-terminal components of the pp1ab polyprotein, contain the core enzymatic activities necessary for viral replication.^[1] After proteolytic processing, several of the nonstructural proteins assemble into a large protein complex known as the replicase-transcriptase complex (RTC) which performs genome replication and transcription.^[1][2]

main protease flanked on either end by transmembrane domains; and from ORF1b, a nucleotidyltransferase domain known as NiRAN, RNA-dependent RNA polymerase (RdRp), a zinc-binding domain, and a helicase.^[3][9] (This is sometimes considered seven domains, counting the transmembrane regions separately.^[4]) In addition, an endoribonuclease domain is found in all nidoviruses that infect vertebrate hosts. Arteriviruses, which have smaller genomes than the other nidovirus lineages, also lack methyltransferases as well as a proofreading exoribonuclease, a domain that is conserved in nidoviruses with larger genomes.^[3] This proofreading functionality is thought to be required for sufficient fidelity to replicate large RNA genomes, but may also play additional roles in some viruses.^[9]

gene fusions.^[4] The largest known nidovirus, planarian secretory cell nidovirus (PSCNV), with a 41kb genome, has a non-canonical genome structure in which ORF1a, ORF1b, and downstream ORFs containing structural proteins are fused and expressed as a single large ORF encoding a polyprotein of over 13,000 amino acids.^[4][12] In these non-canonical genomes, other frameshift locations or stop codon readthrough may be used to regulate the stoichiometry of viral proteins.^[4]

arteriviruses with typically 12-15kb genomes to coronaviruses at 27-32kb. Their evolutionary history has been of research interest in understanding the replication of very large RNA genomes despite the relatively low-fidelity replication mechanism of the viral RNA-dependent RNA polymerase (RdRp).^[4] The larger nidovirus genomes (above around 20kb^[3]) encode a proofreading exoribonuclease (nsp14 in coronaviruses) thought to be required for replication fidelity.^[9][1]

sequenced many times, resulting in identification of thousands of distinct variants. In a World Health Organization analysis from July 2020, ORF1ab was the most frequently mutated gene, followed by the S gene encoding the spike protein. The most commonly mutated protein within ORF1ab was papain-like protease (nsp3), and the single most commonly observed missense mutation was in RNA-dependent RNA polymerase.^[13] Some PCR tests that detect COVID-19 analyze the specimen for the ORF1ab gene, among others.^[14]