Flu

Biography

Biography: Yingfang Liu

Abstract

Influenza A virus is an important pathogen accounting for epidemics and pandemics. The existing vaccines and drugs for influenza are unlikely to protect against some new strains emerging from animal reservoirs which possess the potential to cause high mortality. The influenza A RNA-dependent RNA polymerase (RdRP) complex catalyzes viral RNA replication and transcription activities which make it an attractive target for novel antiviral therapy development. The influenza RdRP consists of PB1, PB2 and PA. PB1 was suggested as the core of the RdRP complex, containing the polymerase active sites. PB2 has a cap-binding motif that snatches the 5’cap of host-cell pre-mRNAs. In our previous reports, we found that the N-terminal of PA carries the endonuclease activity. It cleaves the host pre-mRNAs resulting in primers with a 3΄-hydroxyl group for viral transcription. Both structural and functional results implicated that the C-terminal of PA (PA_C) takes part in a diverse range of functions including vRNA/cRNA promoter binding. However, the underlying mechanism of the RdRP complex is elusive due to lacking of whole structure information. Recently, we reconstructed a type A influenza RdRP sub-complex at 4.3 Å resolution using single particle cryo-EM method, compromising PA, PB1 and N-terminal of PB2. The sub-complex folds into a cage-like structure within which PA_C and PB1 creates a partially enclosed central cavity for RNA synthesis. This sub-complex exists as dimer in solution and can assemble into a tetrameric state, regulated by vRNA promoter. Our structural and biochemical results suggest an oligomeric transition model in replication process for influenza RdRP. These results also lead to further understanding of the mechanism of other negative-stranded viral RNA polymerases.