Molecular Basis of the Ternary Interaction between NS1 of the 1918 Influenza A Virus, PI3K, and CRK
Abstract
:1. Introduction
2. Materials and Methods
3. Results and Discussion
3.1. The C-Terminal Tail (CTT) of 1918 Non-Structural Protein 1 (NS1) Directly Binds to CT-10 Regulator of Kinase (CRK)
3.2. The CTT of 1918 NS1 is Structurally Flexible
3.3. 1918 NS1 Forms a Ternary Complex with p85 and CRK
3.4. Molecular Basis of the High Affinity of 1918 NS1:p85 Complex and CRK
Author Contributions
Funding
Conflicts of Interest
References
- Kash, J.C.; Tumpey, T.M.; Proll, S.C.; Carter, V.; Perwitasari, O.; Thomas, M.J.; Basler, C.F.; Palese, P.; Taubenberger, J.K.; García-Sastre, A.; et al. Genomic analysis of increased host immune and cell death responses induced by 1918 influenza virus. Nature 2006, 443, 578–581. [Google Scholar] [CrossRef]
- Krug, R.M. Functions of the influenza a virus ns1 protein in antiviral defense. Curr. Opin. Virol. 2015, 12, 1–6. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- García-Sastre, A.; Egorov, A.; Matassov, D.; Brandt, S.; Levy, D.E.; Durbin, J.E.; Palese, P.; Muster, T. Influenza a virus lacking the ns1 gene replicates in interferon-deficient systems. Virology 1998, 252, 324–330. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Rajsbaum, R.; Albrecht, R.A.; Wang, M.K.; Maharaj, N.P.; Versteeg, G.A.; Nistal-Villán, E.; García-Sastre, A.; Gack, M.U. Species-specific inhibition of rig-i ubiquitination and ifn induction by the influenza a virus ns1 protein. PLoS Pathog. 2012, 8, e1003059. [Google Scholar] [CrossRef]
- Koliopoulos, M.G.; Lethier, M.; van der Veen, A.G.; Haubrich, K.; Hennig, J.; Kowalinski, E.; Stevens, R.V.; Martin, S.R.; Reis, E.; Sousa, C.; et al. Molecular mechanism of influenza a ns1-mediated trim25 recognition and inhibition. Nat. Commun. 2018, 9, 1820. [Google Scholar] [CrossRef]
- Engel, D.A. The influenza virus ns1 protein as a therapeutic target. Antivir. Res. 2013, 99, 409–416. [Google Scholar] [CrossRef] [Green Version]
- Kleinpeter, A.B.; Jureka, A.S.; Falahat, S.M.; Green, T.J.; Petit, C.M. Structural analyses reveal the mechanism of inhibition of influenza virus ns1 by two antiviral compounds. J. Biol. Chem. 2018, 293, 14659–14668. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Basu, D.; Walkiewicz, M.P.; Frieman, M.; Baric, R.S.; Auble, D.T.; Engel, D.A. Novel influenza virus ns1 antagonists block replication and restore innate immune function. J. Virol. 2009, 83, 1881–1891. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Hale, B.G. Conformational plasticity of the influenza a virus ns1 protein. J. Gen. Virol. 2014, 95, 2099–2105. [Google Scholar] [CrossRef]
- Carrillo, B.; Choi, J.M.; Bornholdt, Z.A.; Sankaran, B.; Rice, A.P.; Prasad, B.V. The influenza a virus protein ns1 displays structural polymorphism. J. Virol. 2014, 88, 4113–4122. [Google Scholar] [CrossRef] [Green Version]
- Hale, B.G.; Jackson, D.; Chen, Y.H.; Lamb, R.A.; Randall, R.E. Influenza a virus ns1 protein binds p85beta and activates phosphatidylinositol-3-kinase signaling. Proc. Natl. Acad. Sci. USA 2006, 103, 14194–14199. [Google Scholar] [CrossRef] [Green Version]
- Hrincius, E.R.; Hennecke, A.K.; Gensler, L.; Nordhoff, C.; Anhlan, D.; Vogel, P.; McCullers, J.A.; Ludwig, S.; Ehrhardt, C. A single point mutation (y89f) within the non-structural protein 1 of influenza a viruses limits epithelial cell tropism and virulence in mice. Am. J. Pathol. 2012, 180, 2361–2374. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- 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 2010, 107, 1954–1959. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Ehrhardt, C.; Wolff, T.; Pleschka, S.; Planz, O.; Beermann, W.; Bode, J.G.; Schmolke, M.; Ludwig, S. Influenza a virus ns1 protein activates the pi3k/akt pathway to mediate antiapoptotic signaling responses. J. Virol. 2007, 81, 3058–3067. [Google Scholar] [CrossRef] [Green Version]
- Shin, Y.K.; Liu, Q.; Tikoo, S.K.; Babiuk, L.A.; Zhou, Y. Influenza a virus ns1 protein activates the phosphatidylinositol 3-kinase (pi3k)/akt pathway by direct interaction with the p85 subunit of pi3k. J. Gen. Virol. 2007, 88, 13–18. [Google Scholar] [CrossRef] [PubMed]
- Xing, Z.; Cardona, C.J.; Adams, S.; Yang, Z.; Li, J.; Perez, D.; Woolcock, P.R. 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. 2009, 90, 1109–1118. [Google Scholar] [CrossRef] [PubMed]
- Gallacher, M.; Brown, S.G.; Hale, B.G.; Fearns, R.; Olver, R.E.; Randall, R.E.; Wilson, S.M. Cation currents in human airway epithelial cells induced by infection with influenza a virus. J. Physiol. 2009, 587, 3159–3173. [Google Scholar] [CrossRef] [PubMed]
- Ayllon, J.; Hale, B.G.; García-Sastre, A. Strain-specific contribution of ns1-activated phosphoinositide 3-kinase signaling to influenza a virus replication and virulence. J. Virol. 2012, 86, 5366–5370. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Ayllon, J.; García-Sastre, A.; Hale, B.G. Influenza a viruses and pi3k: Are there time, place and manner restrictions? Virulence 2012, 3, 411–414. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Zhirnov, O.P.; Klenk, H.D. Control of apoptosis in influenza virus-infected cells by upregulation of akt and p53 signaling. Apotosis 2007, 12, 1419–1432. [Google Scholar] [CrossRef]
- Kuo, R.L.; Zhao, C.; Malur, M.; Krug, R.M. Influenza a virus strains that circulate in humans differ in the ability of their ns1 proteins to block the activation of irf3 and interferon-β transcription. Virology 2010, 408, 146–158. [Google Scholar] [CrossRef]
- Heikkinen, L.S.; Kazlauskas, A.; Melén, K.; Wagner, R.; Ziegler, T.; Julkunen, I.; Saksela, K. Avian and 1918 spanish influenza a virus ns1 proteins bind to crk/crkl src homology 3 domains to activate host cell signaling. J. Biol. Chem. 2008, 283, 5719–5727. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Lopes, A.M.; Domingues, P.; Zell, R.; Hale, B.G. Structure-guided functional annotation of the influenza a virus ns1 protein reveals dynamic evolution of the p85β-binding site during circulation in humans. J. Virol. 2017, 91, e01017–e01081. [Google Scholar] [CrossRef] [Green Version]
- Kochs, G.; García-Sastre, A.; Martínez-Sobrido, L. Multiple anti-interferon actions of the influenza a virus ns1 protein. J. Virol. 2007, 81, 7011–7021. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Jureka, A.S.; Kleinpeter, A.B.; Cornilescu, G.; Cornilescu, C.C.; Petit, C.M. Structural basis for a novel interaction between the ns1 protein derived from the 1918 influenza virus and rig-i. Structure 2015, 23, 2001–2010. [Google Scholar] [CrossRef] [Green Version]
- Geiss, G.K.; Salvatore, M.; Tumpey, T.M.; Carter, V.S.; Wang, X.; Basler, C.F.; Taubenberger, J.K.; Bumgarner, R.E.; Palese, P.; Katze, M.G.; et al. Cellular transcriptional profiling in influenza a virus-infected lung epithelial cells: The role of the nonstructural ns1 protein in the evasion of the host innate defense and its potential contribution to pandemic influenza. Proc. Natl. Acad. Sci. USA 2002, 99, 10736–10741. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Cho, J.H.; Zhao, B.; Shi, J.; Savage, N.; Shen, Q.; Byrnes, J.; Yang, L.; Hwang, W.; Li, P. Molecular recognition of a host protein by ns1 of pandemic and seasonal influenza a viruses. Proc. Natl. Acad. Sci. USA 2020, in press. [Google Scholar] [CrossRef]
- Ylösmäki, L.; Fagerlund, R.; Kuisma, I.; Julkunen, I.; Saksela, K. Nuclear translocation of crk adaptor proteins by the influenza a virus ns1 protein. Viruses 2016, 8, 101. [Google Scholar] [CrossRef] [Green Version]
- Ylösmäki, L.; Schmotz, C.; Ylösmäki, E.; Saksela, K. Reorganization of the host cell crk(l)-pi3 kinase signaling complex by the influenza a virus ns1 protein. Virology 2015, 484, 146–152. [Google Scholar] [CrossRef] [Green Version]
- Birge, R.B.; Kalodimos, C.G.; Inagaki, F.; Tanaka, S. Crk and crkl adaptor proteins: Networks for physiological and pathological signaling. Cell Commun. Signal. 2009, 7, 13. [Google Scholar] [CrossRef] [Green Version]
- Shen, Q.; Zeng, D.; Zhao, B.; Bhatt, V.S.; Li, P.; Cho, J.H. The molecular mechanisms underlying the hijack of host proteins by the 1918 spanish influenza virus. ACS Chem. Biol. 2017, 12, 1199–1203. [Google Scholar] [CrossRef] [PubMed]
- Hrincius, E.R.; Liedmann, S.; Finkelstein, D.; Vogel, P.; Gansebom, S.; Ehrhardt, C.; Ludwig, S.; Hains, D.S.; Webby, R.; McCullers, J.A. Nonstructural protein 1 (ns1)-mediated inhibition of c-abl results in acute lung injury and priming for bacterial co-infections: Insights into 1918 h1n1 pandemic? J. Infect. Dis. 2015, 211, 1418–1428. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Hrincius, E.R.; Liedmann, S.; Anhlan, D.; Wolff, T.; Ludwig, S.; Ehrhardt, C. Avian influenza viruses inhibit the major cellular signalling integrator c-abl. Cell Microbiol. 2014, 16, 1854–1874. [Google Scholar] [CrossRef] [PubMed]
- Ferrage, F.; Reichel, A.; Battacharya, S.; Cowburn, D.; Ghose, R. On the measurement of 15n-{1h} nuclear overhauser effects. 2. Effects of the saturation scheme and water signal suppression. J. Magn. Reson. 2010, 207, 294–303. [Google Scholar] [CrossRef] [Green Version]
- Delaglio, F.; Grzesiek, S.; Vuister, G.W.; Zhu, G.; Pfeifer, J.; Bax, A. Nmrpipe: A multidimensional spectral processing system based on unix pipes. J. Biomol. NMR 1995, 6, 277–293. [Google Scholar] [CrossRef]
- Ayllon, J.; Russell, R.J.; García-Sastre, A.; Hale, B.G. Contribution of ns1 effector domain dimerization to influenza a virus replication and virulence. J. Virol. 2012, 86, 13095–13098. [Google Scholar] [CrossRef] [Green Version]
- Aramini, J.M.; Ma, L.C.; Zhou, L.; Schauder, C.M.; Hamilton, K.; Amer, B.R.; Mack, T.R.; Lee, H.W.; Ciccosanti, C.T.; Zhao, L.; et al. Dimer interface of the effector domain of non-structural protein 1 from influenza a virus: An interface with multiple functions. J. Biol. Chem. 2011, 286, 26050–26060. [Google Scholar] [CrossRef] [Green Version]
- Kerry, P.S.; Ayllon, J.; Taylor, M.A.; Hass, C.; Lewis, A.; García-Sastre, A.; Randall, R.E.; Hale, B.G.; Russell, R.J. A transient homotypic interaction model for the influenza a virus ns1 protein effector domain. PLoS ONE 2011, 6, e17946. [Google Scholar] [CrossRef] [Green Version]
- Shen, Q.; Shi, J.; Zeng, D.; Li, P.; Hwang, W.; Cho, J.H. Molecular mechanisms of tight binding through fuzzy interactions. Biophys. J. 2018, 114, 1313–1320. [Google Scholar] [CrossRef] [Green Version]
- Cavanagh, J.; Fairbrother, W.J.; Palmer, A.G.R.; Rance, M.; Skelton, N.J. Protein NMR Spectroscopy, 2nd ed.; Elsevier Academic Press: Cambridge, MA, USA, 2007. [Google Scholar]
- Palmer, A.G.R. Chemical exchange in biomacromolecules: Past, present, and future. J. Magn. Reson. 2014, 241, 3–17. [Google Scholar] [CrossRef] [Green Version]
- Mittermaier, A.; Kay, L.E. New tools provide new insights in nmr studies of protein dynamics. Science 2006, 312, 224–228. [Google Scholar] [CrossRef] [Green Version]
- Sattler, M.; Salgia, R.; Shrikhande, G.; Verma, S.; Pisick, E.; Prasad, K.V.; Griffin, J.D. Steel factor induces tyrosine phosphorylation of crkl and binding of crkl to a complex containing c-kit, phosphatidylinositol 3-kinase, and p120(cbl). J. Biol. Chem. 1997, 272, 10248–10253. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Sattler, M.; Salgia, R. Role of the adapter protein crkl in signal transduction of normal hematopoietic and bcr/abl-transformed cells. Leukemia 1998, 12, 637–644. [Google Scholar] [CrossRef] [Green Version]
- Gelkop, S.; Babichev, Y.; Isakov, N. T cell activation induces direct binding of the crk adapter protein to the regulatory subunit of phosphatidylinositol 3-kinase (p85) via a complex mechanism involving the cbl protein. J. Biol. Chem. 2001, 276, 36174–36182. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Bhatt, V.S.; Zeng, D.; Krieger, I.; Sacchettini, J.C.; Cho, J.H. Binding mechanism of the n-terminal sh3 domain of crkii and proline-rich motifs in cabl. Biophys. J. 2016, 110, 2630–2641. [Google Scholar] [CrossRef] [Green Version]
- Knudsen, B.S.; Zheng, J.; Feller, S.M.; Mayer, J.P.; Burrell, S.K.; Cowburn, D.; Hanafusa, H. Affinity and specificity requirements for the first src homology 3 domain of the crk proteins. EMBO J. 1995, 14, 2191–2198. [Google Scholar] [CrossRef] [PubMed]
- Wu, X.; Knudsen, B.; Feller, S.M.; Zheng, J.; Sali, A.; Cowburn, D.; Hanafusa, H.; Kuriyan, J. Structural basis for the specific interaction of lysine-containing proline-rich peptides with the n-terminal sh3 domain of c-crk. Structure 1995, 3, 215–226. [Google Scholar] [CrossRef] [Green Version]
- Borg, M.; Mittag, T.; Pawson, T.; Tyers, M.; Forman-Kay, J.D.; Chan, H.S. Polyelectrostatic interactions of disordered ligands suggest a physical basis for ultrasensitivity. Proc. Natl. Acad. Sci. USA 2007, 104, 9650–9655. [Google Scholar] [CrossRef] [Green Version]
- Sharma, R.; Raduly, Z.; Miskei, M.; Fuxreiter, M. Fuzzy complexes: Specific binding without complete folding. FEBS Lett. 2015, 589, 2533–2542. [Google Scholar] [CrossRef] [Green Version]
© 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
Share and Cite
Dubrow, A.; Lin, S.; Savage, N.; Shen, Q.; Cho, J.-H. Molecular Basis of the Ternary Interaction between NS1 of the 1918 Influenza A Virus, PI3K, and CRK. Viruses 2020, 12, 338. https://doi.org/10.3390/v12030338
Dubrow A, Lin S, Savage N, Shen Q, Cho J-H. Molecular Basis of the Ternary Interaction between NS1 of the 1918 Influenza A Virus, PI3K, and CRK. Viruses. 2020; 12(3):338. https://doi.org/10.3390/v12030338
Chicago/Turabian StyleDubrow, Alyssa, Sirong Lin, Nowlan Savage, Qingliang Shen, and Jae-Hyun Cho. 2020. "Molecular Basis of the Ternary Interaction between NS1 of the 1918 Influenza A Virus, PI3K, and CRK" Viruses 12, no. 3: 338. https://doi.org/10.3390/v12030338