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

Kerry, P.S., Ayllon, J., Taylor, M.A., Hass, C., Lewis, A., García-Sastre, A., Randall, R.E., Hale, B.G. and Russell, R.J. (2011) A transient homotypic interaction model for the influenza A virus NS1 protein effector domain. PLoS ONE, 6(3), e17946. (doi: 10.1371/journal.pone.0017946) (PMID:21464929) (PMCID:PMC3065461)

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.

• Item Type: Articles
• Keywords: Influenza
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Hale, Dr Benjamin
• Authors: Kerry, P.S., Ayllon, J., Taylor, M.A., Hass, C., Lewis, A., García-Sastre, A., Randall, R.E., Hale, B.G., and Russell, R.J.
• Subjects: Q Science > Q Science (General); Q Science > QH Natural history > QH345 Biochemistry; Q Science > QR Microbiology > QR355 Virology
• College/School: College of Medical Veterinary and Life Sciences > School of Infection & Immunity
• Journal Name: PLoS ONE
• Publisher: Public Library of Science
• ISSN: 1932-6203
• ISSN (Online): 1932-6203
• Published Online: 28 March 2011
• Copyright Holders: Copyright © 2011 The Authors
• First Published: First published in PLoS ONE 6(3):e17946
• Publisher Policy: Reproduced under a Creative Commons Licence