Structure and nuclear import function of the C-terminal domain of influenza virus polymerase PB2 subunit

Tarendeau, F.; Boudet, Julien; Guilligay, Delphine; Mas, Philippe J.; Bougault, Catherine; Boulo, Sébastien; Baudin, Florence; Ruigrok, Rob W.H.; Daigle, Nathalie; Ellenberg, Jan; Cusack, Stephen; Simorre, Jean-Pierre; Hart, Darren J.

doi:10.1038/nsmb1212

Cited by 288 publications

(379 citation statements)

References 32 publications

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“…Conversely, PB2 mutants with the negatively charged glutamic acid or aspartic acid at position 627 are impaired. Structural analysis has shown that K627 is located on a large solventexposed face of the protein with a predominant positively charged surface (36). Introduction of the E627 mutation disrupted the positively charged surface without altering the structure.…”

Section: Discussionmentioning

confidence: 99%

Adaptive strategies of the influenza virus polymerase for replication in humans

Mehle¹,

Doudna

2009

Proc. Natl. Acad. Sci. U.S.A.

343

373

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Transmission of influenza viruses into the human population requires surmounting barriers to cross-species infection. Changes in the influenza polymerase overcome one such barrier. Viruses isolated from birds generally contain polymerases with the aviansignature glutamic acid at amino acid 627 in the PB2 subunit. These polymerases display restricted activity in human cells. An adaptive change in this residue from glutamic acid to the human-signature lysine confers high levels of polymerase activity in human cells. This mutation permits escape from a species-specific restriction factor that targets polymerases from avian viruses. A 2009 swineorigin H1N1 influenza A virus recently established a pandemic infection in humans, even though the virus encodes a PB2 with the restrictive glutamic acid at amino acid 627. We show here that the 2009 H1N1 virus has acquired second-site suppressor mutations in its PB2 polymerase subunit that convey enhanced polymerase activity in human cells. Introduction of this polymorphism into the PB2 subunit of a primary avian isolate also increased polymerase activity and viral replication in human and porcine cells. An alternate adaptive strategy has also been identified, whereby introduction of a human PA subunit into an avian polymerase overcomes restriction in human cells. These data reveal a strategy used by the 2009 H1N1 influenza A virus and identify other pathways by which avian and swine-origin viruses may evolve to enhance replication, and potentially pathogenesis, in humans.2009 A(H1N1) ͉ PB2 ͉ species barriers

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Section: Discussionmentioning

confidence: 99%

Adaptive strategies of the influenza virus polymerase for replication in humans

Mehle¹,

Doudna

2009

Proc. Natl. Acad. Sci. U.S.A.

343

373

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“…2). In addition to the subunit interfaces mentioned above, the atomic structures of domains of the PA and PB2 subunits have been determined 47,55,56,[63][64][65][66][67] but no information on the structure of the polymerase active site in the PB1 subunit is yet available. The data reported allowed the identification of the polymerase cap-binding site in PB2 and established that the endonuclease responsible for cap-snatching resides at the N-terminal region of PA, in agreement with previous genetic contacts detected in the cryo-EM structure of the mini-RNP.…”

Section: ©2 0 1 1 L a N D E S B I O S C I E N C E D O N O T D I S Tmentioning

confidence: 99%

The influenza virus RNA synthesis machine

et al. 2011

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“…Co-crystal structures of both S. cerevisiae and M. musculus importin-a have been solved in complex with various NLS peptides (52)(53)(54)(55)(56)(57)(58)(59). The three-dimensional structures reveal that NLS peptides bind specifically in two binding grooves created by flexible armadillo (ARM) motifs in the central domain of importin-a (54, 55).…”

Section: Classical Nls Sequencesmentioning

confidence: 99%

Nuclear localization signals and human disease

McLane

Corbett

2009

IUBMB Life

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SummaryIn eukaryotic cells, the physical separation of the genetic material in the nucleus from the translation and signaling machinery in the cytoplasm by the nuclear envelope creates a requirement for a mechanism through which macromolecules can enter or exit the nucleus as necessary. Nucleocytoplasmic transport involves the specific recognition of cargo molecules by transport receptors in one compartment followed by the physical relocation of that cargo into the other compartment through regulated pores that perforate the nuclear envelope. The recognition of protein cargoes by their transport receptors occurs via amino acid sequences in cargo proteins called nuclear targeting signals. Both nuclear import and export of proteins are highly regulated processes that control, not only what cargo can enter and/or exit the nucleus, but also when in the cell cycle and in what cell type, the cargo can be transported. Deregulation of the nuclear transport of specific cargoes has been linked to numerous cancers and developmental disorders highlighting the importance of understanding the mechanisms underlying nucleocytoplasmic transport and particularly the modulation of the specific interactions between transporter receptors and nuclear targeting signals within target cargo proteins.2009 IUBMB IUBMB Life, 61(7): [697][698][699][700][701][702][703][704][705][706] 2009

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Structure and nuclear import function of the C-terminal domain of influenza virus polymerase PB2 subunit

Cited by 288 publications

References 32 publications

Adaptive strategies of the influenza virus polymerase for replication in humans

Adaptive strategies of the influenza virus polymerase for replication in humans

The influenza virus RNA synthesis machine

Nuclear localization signals and human disease

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