Journal
SCIENTIFIC REPORTS
Volume 6, Issue -, Pages -Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/srep24727
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Funding
- Hofmann-La Roche pRED external collaboration program
- Region Rhone-Alpes (ARC 1 Sante)
- Labex GRAL
- French agency for Research [ANR-2010-Blanc-1307-1301, ANR-14-CE09-0017, 259751]
- ComplexINC [279039]
- FRISBI [ANR-10-INSB-05-02]
- GRAL [ANR-10-LABX-49-01]
- Agence Nationale de la Recherche (ANR) [ANR-14-CE09-0017] Funding Source: Agence Nationale de la Recherche (ANR)
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The genome of influenza A virus (IAV) comprises eight RNA segments (vRNA) which are transcribed and replicated by the heterotrimeric IAV RNA-dependent RNA-polymerase (RdRp). RdRp consists of three subunits (PA, PB1 and PB2) and binds both the highly conserved 3'-and 5'-ends of the vRNA segment. The IAV RdRp is an important antiviral target, but its structural mechanism has remained largely elusive to date. By applying a polyprotein strategy, we produced RdRp complexes and define a minimal human IAV RdRp core complex. We show that PA-PB1 forms a stable heterodimeric submodule that can strongly interact with 5'-vRNA. In contrast, 3'-vRNA recognition critically depends on the PB2 N-terminal domain. Moreover, we demonstrate that PA-PB1 forms a stable and stoichiometric complex with host nuclear import factor RanBP5 that can be modelled using SAXS and we show that the PAPB1- RanPB5 complex is no longer capable of 5'-vRNA binding. Our results provide further evidence for a step-wise assembly of IAV structural components, regulated by nuclear transport mechanisms and host factor binding.
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