Structures of influenza A and B replication complexes explain avian to human host adaption and reveal a role of ANP32 as an electrostatic chaperone for the apo-polymerase.

Cusack, S.; Arragain, B.; Krischuns, T.; Pelosse, M.; Drncova, P.; Blackledge, M.; Naffakh, N.

doi:10.1101/2024.04.20.590211

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bioRxiv · 10.1101/2024.04.20.590211

Structures of influenza A and B replication complexes explain avian to human host adaption and reveal a role of ANP32 as an electrostatic chaperone for the apo-polymerase.

Cusack, S.·Arragain, B.·Krischuns, T.·Pelosse, M.·Drncova, P.·Blackledge, M.·Naffakh, N.

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Abstract

Replication of influenza viral RNA depends on at least two viral polymerases, a parental replicase and an encapsidase, and cellular factor ANP32. ANP32 comprises an LRR domain and a long C-terminal low complexity acidic region (LCAR). Here we show that ANP32 is recruited to the replication complex (replicase-ANP32-encapsidase) by first acting as an electrostatic chaperone to stabilise the encapsidase moiety within apo-polymerase symmetric dimers that are distinct for influenza A and B polymerases. The encapsidase, with ANP32, then forms an asymmetric complex with the replicase. Cryo-EM structures of the influenza A and B replication complexes give new insight into the mutations known to adapt avian strain polymerases to use the distinct ANP32 in mammalian cells. The cryo-EM map of the FluPolB complex shows extra density attributable to the ANP32 LCAR wrapping around and stabilising the apo-encapsidase conformation. These results suggest a functional requirement for three polymerases for replication.

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Cusack, S., Arragain, B., Krischuns, T., Pelosse, M., Drncova, P., Blackledge, M., Naffakh, N.. 2024-04-20. Structures of influenza A and B replication complexes explain avian to human host adaption and reveal a role of ANP32 as an electrostatic chaperone for the apo-polymerase.. https://doi.org/10.1101/2024.04.20.590211

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