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

[tetano]

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

Stefan Reich1, 2, n1
Delphine Guilligay1, 2, n1
Alexander Pflug1, 2, n1
Hélène Malet1, 2,
Imre Berger1, 2,
Thibaut Crépin2,
Darren Hart1, 2,
Thomas Lunardi1, 2,
Max Nanao1, 2,
Rob W. H. Ruigrok2,
Stephen Cusack1, 2,

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Corresponding author

Nature
(2014)
doi:10.1038/nature14009


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.

http://www.nature.com/nature/journal/vaop/ncurrent/full/nature14009.html

 

[tetano]

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

Structure of influenza A polymerase bound to the viral RNA promoter

Alexander Pflug1, 2, n1
Delphine Guilligay1, 2, n1
Stefan Reich1, 2, n1
Stephen Cusack1, 2,



Nature
(2014)
doi:10.1038/nature14008



The influenza virus polymerase transcribes or replicates the segmented RNA genome (viral RNA) into viral messenger RNA or full-length copies. To initiate RNA synthesis, the polymerase binds to the conserved 3′ and 5′ extremities of the viral RNA. Here we present the crystal structure of the heterotrimeric bat influenza A polymerase, comprising subunits PA, PB1 and PB2, bound to its viral RNA promoter. PB1 contains a canonical RNA polymerase fold that is stabilized by large interfaces with PA and PB2. The PA endonuclease and the PB2 cap-binding domain, involved in transcription by cap-snatching, form protrusions facing each other across a solvent channel. The 5′ extremity of the promoter folds into a compact hook that is bound in a pocket formed by PB1 and PA close to the polymerase active site. This structure lays the basis for an atomic-level mechanistic understanding of the many functions of influenza polymerase, and opens new opportunities for anti-influenza drug design.

http://www.nature.com/nature/journal/vaop/ncurrent/full/nature14008.html