A transient homotypic interaction model for the influenza A virus NS1 protein effector domain

Philip S. Kerry, Juan Ayllon, Margaret A. Taylor, Claudia Hass, Andrew Lewis, Adolfo Garcia-Sastre, Richard E. Randall, Benjamin G. Hale, Rupert J. Russell

Research output: Contribution to journalArticlepeer-review

37 Citations (Scopus)
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Influenza A virus NS1 protein is a multifunctional virulence factor consisting of an RNA binding domain (RBD), a short linker, an effector domain (ED), and a C-terminal 'tail'. Although poorly understood, NS1 multimerization may autoregulate its actions. While RBD dimerization seems functionally conserved, two possible apo ED dimers have been proposed (helix-helix and strand-strand). Here, we analyze all available RBD, ED, and full-length NS1 structures, including four novel crystal structures obtained using EDs from divergent human and avian viruses, as well as two forms of a monomeric ED mutant. The data reveal the helix-helix interface as the only strictly conserved ED homodimeric contact. Furthermore, a mutant NS1 unable to form the helix-helix dimer is compromised in its ability to bind dsRNA efficiently, implying that ED multimerization influences RBD activity. Our bioinformatical work also suggests that the helix-helix interface is variable and transient, thereby allowing two ED monomers to twist relative to one another and possibly separate. In this regard, we found a mAb that recognizes NS1 via a residue completely buried within the ED helix-helix interface, and which may help highlight potential different conformational populations of NS1 (putatively termed 'helix-closed' and 'helix-open') in virus-infected cells. 'Helix-closed' conformations appear to enhance dsRNA binding, and 'helix-open' conformations allow otherwise inaccessible interactions with host factors. Our data support a new model of NS1 regulation in which the RBD remains dimeric throughout infection, while the ED switches between several quaternary states in order to expand its functional space. Such a concept may be applicable to other small multifunctional proteins.

Original languageEnglish
Article numbere17946
Number of pages13
JournalPLoS One
Issue number3
Publication statusPublished - 28 Mar 2011


  • Double-stranded-rna
  • X-ray-structure
  • Nonstructural protein-1
  • Iinfected-cells
  • Structural basis
  • Binding motif
  • Interferon
  • Activation
  • Dimerization
  • Recognition


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