Identification of DEDD- and PHP-Superfamilies of Proofreading Exonucleases in the Acidic Protein Subunit PA of RNA Polymerase of Human Influenza Viruses

Abstract

RNA polymerase from human influenza viruses A, B and C is a heterotrimric enzyme, made up of three different subunits. It performs the crucial function of both genome replication as well as transcription. One of the RNA polymerase subunits, the polymerase acidic protein subunit (PA), is suggested to function as an endonuclease in a ‘cap-snatching’ mechanism, unique to influenza viruses. However, by multiple sequence alignment (MSA) analysis, it was found that the PA subunits of the polymerases do harbour typical proofreading (PR) DEDD-superfamily of exonuclease active site in all three viruses. However, in human influenza A virus, an additional putative PR exonuclease active site amino acids belonging to Polymerase-Histidinol Phosphatase (PHP)-superfamily are identified. The identified active site amino acids data are in close agreement with the similar DEDD- and PHP-superfamilies of PR exonucleases, already reported from both DNA-dependent RNA polymerases (DdRps) and RNA-dependent RNA polymerases (RdRps) from prokaryotes, eukaryotes and RNA viruses. The putative PHP–family PR exonuclease active site, identified by MSA analysis, is also in close agreement to the already reported PHP–family of PR exonuclease active sites from DdDps of replicases and pol X polymerases of the bacterial kingdom. Only in the pandemic causing human influenza A virus, the putative PHP-family PR exonuclease domain is found along with the DEDD-family PR exonuclease domain.