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Please use this identifier to cite or link to this item: http://hdl.handle.net/10023/2177
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Title: A transient homotypic interaction model for the influenza A virus NS1 protein effector domain
Authors: Kerry, Philip S.
Ayllon, Juan
Taylor, Margaret A.
Hass, Claudia
Lewis, Andrew
Garcia-Sastre, Adolfo
Randall, Richard E.
Hale, Benjamin G.
Russell, Rupert J.
Keywords: Double-stranded-rna
X-ray-structure
Nonstructural protein-1
Iinfected-cells
Structural basis
Binding motif
Interferon
Activation
Dimerization
Recognition
QR355 Virology
Issue Date: 28-Mar-2011
Citation: Kerry , P S , Ayllon , J , Taylor , M A , Hass , C , Lewis , A , Garcia-Sastre , A , Randall , R E , Hale , B G & Russell , R J 2011 , ' A transient homotypic interaction model for the influenza A virus NS1 protein effector domain ' PLoS One , vol 6 , no. 3 , e17946 .
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.
Version: Publisher PDF
Description: Work in St. Andrews was supported by the Medical Research Council, UK (RER and RJR), and the Scottish Funding Council (RJR).
Status: Peer reviewed
URI: http://hdl.handle.net/10023/2177
DOI: http://dx.doi.org/10.1371/journal.pone.0017946
ISSN: 1932-6203
Type: Journal article
Rights: © 2011 Kerry et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Appears in Collections:University of St Andrews Research
Biology Research
Physics & Astronomy Research
Biomedical Sciences Research Complex (BSRC) Research



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