ORF1a1ab

ORF1a and ORF1ab are two overlapping open reading frames at the 5' end of coronavirus genomes, often referred to collectively as ORF1a/ORF1ab. They encode the large non-structural polyproteins that are essential for viral replication and transcription. The ORF1a region is translated directly to produce polyprotein pp1a, while a −1 ribosomal frameshift at a slippery sequence, aided by a downstream RNA pseudoknot, allows continuation into ORF1b to produce the extended polyprotein pp1ab. This mechanism yields two principal products in different abundances.

Following translation, both pp1a and pp1ab are proteolytically cleaved into 16 non-structural proteins (nsp1–nsp16) by viral proteases. The cleavage is performed mainly by the papain-like protease in nsp3 and the 3C-like protease in nsp5. The resulting NSPs assemble to form the replication-transcription complex and other factors required for RNA synthesis, genome repair, and processing of viral RNA.

The non-structural proteins derived from ORF1a/ORF1ab carry out diverse functions central to viral replication. Key activities include RNA-dependent RNA polymerase activity (nsp12) with cofactors (nsp7 and nsp8), helicase (nsp13), proofreading exonuclease (nsp14), endoribonuclease (nsp15), and various methyltransferases involved in RNA capping (e.g., nsp16) along with multiple supporting roles. The proper processing and function of these NSPs are critical for efficient viral replication.

ORF1a/ORF1ab are highly conserved among coronaviruses and represent a core component of the replication machinery. Variations in this region can influence frameshifting efficiency, polyprotein processing, and replication dynamics across different coronavirus species.