HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

J. Biol. Chem., Vol. 283, Issue 3, 1372-1380, January 18, 2008

This Article Full Text Full Text (PDF) All Versions of this Article: 283/3/1372    most recent M708862200v1 Submit a Letter to Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Hale, B. G. Articles by Randall, R. E. Search for Related Content PubMed PubMed Citation Articles by Hale, B. G. Articles by Randall, R. E. Social Bookmarking                      What's this?

Binding of Influenza A Virus NS1 Protein to the Inter-SH2 Domain of p85β Suggests a Novel Mechanism for Phosphoinositide 3-Kinase Activation^*

Benjamin G. Hale¹, Ian H. Batty, C. Peter Downes, and Richard E. Randall

From the Centre for Biomolecular Sciences, University of St. Andrews, St. Andrews, Fife KY16 9ST, United Kingdom and the Division of Molecular Physiology, Faculty of Life Sciences, University of Dundee, Dundee DD1 5EH, United Kingdom

Influenza A virus NS1 protein stimulates host-cell phosphoinositide 3-kinase (PI3K) signaling by binding to the p85β regulatory subunit of PI3K. Here, in an attempt to establish a mechanism for this activation, we report further on the functional interaction between NS1 and p85β. Complex formation was found to be independent of NS1 RNA binding activity and is mediated by the C-terminal effector domain of NS1. Intriguingly, the primary direct binding site for NS1 on p85β is the inter-SH2 domain, a coiled-coil structure that acts as a scaffold for the p110 catalytic subunit of PI3K. In vitro kinase activity assays, together with protein binding competition studies, reveal that NS1 does not displace p110 from the inter-SH2 domain, and indicate that NS1 can form an active heterotrimeric complex with PI3K. In addition, it was established that residues at the C terminus of the inter-SH2 domain are essential for mediating the interaction between p85β and NS1. Equivalent residues in p85 have previously been implicated in the basal inhibition of p110. However, such p85 residues were unable to substitute for those in p85β with regards NS1 binding. Overall, these data suggest a model by which NS1 activates PI3K catalytic activity by masking a normal regulatory element specific to the p85β inter-SH2 domain.

Received for publication, October 26, 2007 , and in revised form, November 19, 2007.

^* This work was supported by the Medical Research Council, UK. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement"in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Centre for Biomolecular Sciences, University of St. Andrews, St. Andrews, Fife KY16 9ST, UK. Tel.: 44-1334-463407; Fax: 44-1334-462595; E-mail: bgh1{at}st-andrews.ac.uk.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

				Z. Xing, C. J. Cardona, S. Adams, Z. Yang, J. Li, D. Perez, and P. R. Woolcock Differential regulation of antiviral and proinflammatory cytokines and suppression of Fas-mediated apoptosis by NS1 of H9N2 avian influenza virus in chicken macrophages J. Gen. Virol., May 1, 2009; 90(5): 1109 - 1118. [Abstract] [Full Text] [PDF]

				B. G. Hale, R. E. Randall, J. Ortin, and D. Jackson The multifunctional NS1 protein of influenza A viruses J. Gen. Virol., October 1, 2008; 89(10): 2359 - 2376. [Abstract] [Full Text] [PDF]

				K. Das, L.-C. Ma, R. Xiao, B. Radvansky, J. Aramini, L. Zhao, J. Marklund, R.-L. Kuo, K. Y. Twu, E. Arnold, et al. Structural basis for suppression of a host antiviral response by influenza A virus PNAS, September 2, 2008; 105(35): 13093 - 13098. [Abstract] [Full Text] [PDF]

				A. Alminaite, V. Backstrom, A. Vaheri, and A. Plyusnin Oligomerization of hantaviral nucleocapsid protein: charged residues in the N-terminal coiled-coil domain contribute to intermolecular interactions J. Gen. Virol., September 1, 2008; 89(9): 2167 - 2174. [Abstract] [Full Text] [PDF]

				Y. Li, D. H. Anderson, Q. Liu, and Y. Zhou Mechanism of Influenza A Virus NS1 Protein Interaction with the p85{beta}, but Not the p85{alpha}, Subunit of Phosphatidylinositol 3-Kinase (PI3K) and Up-regulation of PI3K Activity J. Biol. Chem., August 22, 2008; 283(34): 23397 - 23409. [Abstract] [Full Text] [PDF]