3L4Q

Structural insights into phosphoinositide 3-kinase activation by the influenza A virus NS1 protein

Summary for 3L4Q

• Entry DOI: 10.2210/pdb3l4q/pdb
• Descriptor: Non-structural protein 1, Phosphatidylinositol 3-kinase regulatory subunit beta, GLYCEROL, ... (4 entities in total)
• Functional Keywords: pi3k, phosphoinositide-3-kinase, influenza virus, ns1, kinase, viral protein-protein binding complex, viral protein/protein binding
• Biological source: Influenza A virus; More
• Cellular location: Host nucleus: P03496
• Total number of polymer chains: 4
• Total formula weight: 78363.00

Authors

Hale, B.G.,Kerry, P.S.,Jackson, D.,Precious, B.L.,Gray, A.,Killip, M.J.,Randall, R.E.,Russell, R.J. (deposition date: 2009-12-21, release date: 2010-02-02, Last modification date: 2023-11-01)

Primary citation

Hale, B.G.,Kerry, P.S.,Jackson, D.,Precious, B.L.,Gray, A.,Killip, M.J.,Randall, R.E.,Russell, R.J.
Structural insights into phosphoinositide 3-kinase activation by the influenza A virus NS1 protein
Proc.Natl.Acad.Sci.USA, 107:1954-1959, 2010

PubMed Abstract: Seasonal epidemics and periodic worldwide pandemics caused by influenza A viruses are of continuous concern. The viral nonstructural (NS1) protein is a multifunctional virulence factor that antagonizes several host innate immune defenses during infection. NS1 also directly stimulates class IA phosphoinositide 3-kinase (PI3K) signaling, an essential cell survival pathway commonly mutated in human cancers. Here, we present a 2.3-A resolution crystal structure of the NS1 effector domain in complex with the inter-SH2 (coiled-coil) domain of p85beta, a regulatory subunit of PI3K. Our data emphasize the remarkable isoform specificity of this interaction, and provide insights into the mechanism by which NS1 activates the PI3K (p85beta:p110) holoenzyme. A model of the NS1:PI3K heterotrimeric complex reveals that NS1 uses the coiled-coil as a structural tether to sterically prevent normal inhibitory contacts between the N-terminal SH2 domain of p85beta and the p110 catalytic subunit. Furthermore, in this model, NS1 makes extensive contacts with the C2/kinase domains of p110, and a small acidic alpha-helix of NS1 sits adjacent to the highly basic activation loop of the enzyme. During infection, a recombinant influenza A virus expressing NS1 with charge-disruption mutations in this acidic alpha-helix is unable to stimulate the production of phosphatidylinositol 3,4,5-trisphosphate or the phosphorylation of Akt. Despite this, the charge-disruption mutations in NS1 do not affect its ability to interact with the p85beta inter-SH2 domain in vitro. Overall, these data suggest that both direct binding of NS1 to p85beta (resulting in repositioning of the N-terminal SH2 domain) and possible NS1:p110 contacts contribute to PI3K activation.

PubMed: 20133840
DOI: 10.1073/pnas.0910715107

Experimental method

X-RAY DIFFRACTION (2.3 Å)