Projects per year
Abstract
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 language | English |
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Article number | e17946 |
Number of pages | 13 |
Journal | PLoS One |
Volume | 6 |
Issue number | 3 |
DOIs | |
Publication status | Published - 28 Mar 2011 |
Keywords
- Double-stranded-rna
- X-ray-structure
- Nonstructural protein-1
- Iinfected-cells
- Structural basis
- Binding motif
- Interferon
- Activation
- Dimerization
- Recognition
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Dive into the research topics of 'A transient homotypic interaction model for the influenza A virus NS1 protein effector domain'. Together they form a unique fingerprint.Projects
- 2 Finished
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Identification of novel inhibitory: Identification of novel inhibitory compounds of the surface glycoproteins of Influenza viruses using fragment screening
Russell, R. J. M. (PI)
5/05/08 → 4/05/11
Project: Standard
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Virus NS1 - PI3 G0601126: Studies on the interaction of influenza virus NS1 protein with cellular P13-kinase
Randall, R. E. (PI)
1/10/07 → 31/12/10
Project: Standard