PA is a key protein in the influenza virus polymerase complex, although its role was only partly outlined until recently. PA contains an N-terminal endonuclease domain (PAN) that interacts with PB26 and a C-terminal domain (PA-CTD) that interacts with PB1. There have been reports of peptide inhibitors and small molecule inhibitors that bind to PA and disrupt the PA-PB1 interaction.
Polymerase acidic / PA cDNAs
PA can be cleaved by limited tryptic digestion into two domains: a smaller N-terminal domain of ~25 kD and a larger C-terminal of ~55 kD. The two domains are separated by a long linker peptide. Neither the N-terminal nor C-terminal domains of PA could ensure a stable interaction with PB1 without the presence of the linker.
The crystal structure of the N-terminal domain of PA, which has been implicated in a diverse range of functions, such as endonuclease and protease activities.The PAN structure has an α/β architecture with five mixed β-strands (β1-5) forming a twisted plane surrounded by seven α-helices (α1-7). A strongly negatively charged cavity, formed by a concentration of acidic residues, is surrounded by helices α2−α5 and strand β3 and houses a metal binding site. Structural comparison of PAN revealed a close match with other endonucleases, pointing towards PAN as a new member of the (P)DXN(D/E)XK endonuclease superfamily.
Organisation and structure of influenza virus A NEP
The role of PA in the polymerase heterotrimer has only been partly outlined. It has been reported to be required for replication and for transcription of vRNA as well as endonuclease cleavage of the cap RNA primer.
Among its various putative functions, PA was reported to harbour proteolytic activity that can induce generalized proteolysis of both viral and host proteins. PA can lead to degradation of the large subunit of RNA polymerase II complex in host cells, and has also been implicated as a novel serine protease with Ser624 at the active site.
• Spencer O. Moen.Structural analysis of H1N1 and H7N9 influenza A virus PA in the absence of PB1.SCIENTIFIC REPORTS.2014
• LIU YingFang.Structure-function studies of the influenza virus RNA polymerase PA subunit.SCIENCE IN CHINA PRESS.2009
• Chu-Wen Yang.A Comparative Study of Short Linear Motif Compositions of the Influenza A Virus Ribonucleoproteins.PLoS ONE.2012
• Benjamin Ma¨nz. Disruption of the Viral Polymerase Complex Assembly as a Novel Approach to Attenuate Influenza A Virus.THE JOURNAL OF BIOLOGICAL CHEMISTRY.2011