Molecular basis of host-adaptation interactions between influenza virus polymerase PB2 subunit and ANP32A

Nat Commun. 2020 Jul 21;11(1):3656. doi: 10.1038/s41467-020-17407-x.


Avian influenza polymerase undergoes host adaptation in order to efficiently replicate in human cells. Adaptive mutants are localised on the C-terminal (627-NLS) domains of the PB2 subunit. In particular, mutation of PB2 residue 627 from E to K rescues polymerase activity in mammalian cells. A host transcription regulator ANP32A, comprising a long C-terminal intrinsically disordered domain (IDD), is responsible for this adaptation. Human ANP32A IDD lacks a 33 residue insertion compared to avian ANP32A, and this deletion restricts avian influenza polymerase activity. We used NMR to determine conformational ensembles of E627 and K627 forms of 627-NLS of PB2 in complex with avian and human ANP32A. Human ANP32A IDD transiently binds to the 627 domain, exploiting multivalency to maximise affinity. E627 interrupts the polyvalency of the interaction, an effect compensated by an avian-unique motif in the IDD. The observed binding mode is maintained in the context of heterotrimeric influenza polymerase, placing ANP32A in the immediate vicinity of known host-adaptive PB2 mutants.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Avian Proteins / metabolism
  • Avian Proteins / ultrastructure*
  • Birds / virology
  • Humans
  • Influenza A Virus, H5N1 Subtype / genetics
  • Influenza A Virus, H5N1 Subtype / metabolism
  • Influenza A Virus, H5N1 Subtype / pathogenicity*
  • Influenza in Birds / virology
  • Influenza, Human / virology
  • Mutation
  • Nuclear Magnetic Resonance, Biomolecular
  • Nuclear Proteins / metabolism
  • Nuclear Proteins / ultrastructure*
  • Protein Binding / genetics
  • Protein Domains / genetics*
  • RNA-Binding Proteins / metabolism
  • RNA-Binding Proteins / ultrastructure*
  • RNA-Dependent RNA Polymerase / genetics
  • RNA-Dependent RNA Polymerase / metabolism
  • RNA-Dependent RNA Polymerase / ultrastructure*
  • Species Specificity
  • Viral Proteins / genetics
  • Viral Proteins / metabolism
  • Viral Proteins / ultrastructure*
  • Virus Replication


  • ANP32A protein, human
  • Avian Proteins
  • Nuclear Proteins
  • PB2 protein, Influenzavirus A
  • RNA-Binding Proteins
  • Viral Proteins
  • RNA-Dependent RNA Polymerase