Structural insight into cap-snatching and RNA synthesis by influenza polymerase

Nature. 2014 Dec 18;516(7531):361-6. doi: 10.1038/nature14009. Epub 2014 Nov 19.

Abstract

Influenza virus polymerase uses a capped primer, derived by 'cap-snatching' from host pre-messenger RNA, to transcribe its RNA genome into mRNA and a stuttering mechanism to generate the poly(A) tail. By contrast, genome replication is unprimed and generates exact full-length copies of the template. Here we use crystal structures of bat influenza A and human influenza B polymerases (FluA and FluB), bound to the viral RNA promoter, to give mechanistic insight into these distinct processes. In the FluA structure, a loop analogous to the priming loop of flavivirus polymerases suggests that influenza could initiate unprimed template replication by a similar mechanism. Comparing the FluA and FluB structures suggests that cap-snatching involves in situ rotation of the PB2 cap-binding domain to direct the capped primer first towards the endonuclease and then into the polymerase active site. The polymerase probably undergoes considerable conformational changes to convert the observed pre-initiation state into the active initiation and elongation states.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Catalytic Domain
  • Crystallization
  • DNA-Directed RNA Polymerases / chemistry
  • DNA-Directed RNA Polymerases / metabolism*
  • Gene Expression Regulation, Viral
  • Influenza A virus / chemistry
  • Influenza A virus / enzymology*
  • Influenza B virus / chemistry
  • Influenza B virus / enzymology*
  • Models, Molecular*
  • Promoter Regions, Genetic
  • Protein Binding
  • Protein Structure, Tertiary
  • RNA Caps* / chemistry
  • RNA Caps* / metabolism
  • RNA, Viral / biosynthesis*
  • RNA, Viral / chemistry*
  • Virus Replication

Substances

  • RNA Caps
  • RNA, Viral
  • DNA-Directed RNA Polymerases