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The heads of the measles virus attachment protein move to transmit the fusion-triggering signal

Nature Structural & Molecular Biology volume 18, pages 128–134 (2011)Cite this article

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Abstract

The measles virus entry system, consisting of attachment (hemagglutinin, H) and fusion proteins, operates by means of a variety of natural and targeted receptors; however, the mechanism that triggers fusion of the viral envelope with the plasma membrane is not understood. Here, we tested a model proposing that the two heads of an H dimer, which are covalently linked at their base, after binding two receptor molecules, move relative to each other to transmit the fusion-triggering signal. Indeed, stabilizing the H-dimer interface with additional intermolecular disulfide bonds prevented membrane fusion, an effect that was reversed by a reducing agent. Moreover, a membrane-anchored designated receptor efficiently triggered fusion, provided that it engaged the H dimer at locations proximal to where the natural receptors bind and distal to the H-dimer interface. We discuss how receptors may force H-protein heads to switch partners and transmit the fusion-triggering signal.

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Figure 1: Structure and interactions of the measles virus H dimer.
Figure 2: Location of cysteines introduced to constrain the H-dimer interface and evidence of disulfide bond formation.
Figure 3: Constraining the H-dimer interface disrupts fusion.
Figure 4: Positioning hexahistidine tags to direct receptor binding.
Figure 5: Location of receptor-binding site determines efficiency of fusion triggering.

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References

  1. Harrison, S.C. Viral membrane fusion. Nat. Struct. Mol. Biol. 15, 690–698 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Marsh, M. & Helenius, A. Virus entry: open sesame. Cell 124, 729–740 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Chandran, K., Sullivan, N.J., Felbor, U., Whelan, S.P. & Cunningham, J.M. Endosomal proteolysis of the Ebola virus glycoprotein is necessary for infection. Science 308, 1643–1645 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Lamb, R.A. & Parks, G.D. Paramyxovirus: The viruses and their replication. in Fields Virology Vol. 1 (eds. Fields, B., Knipe, D. & Howley, P.) 1305–1340 (Lippincott Williams & Wilkins, Philadelphia, 2007).

  5. Griffin, D.E. Measles viruses. in Fields Virology. Vol. 1 (eds. Knipe, D.M. & Howley, P.M.), 1551–1585 (Lippincott Williams and Wilkins, Philadelphia, 2007).

    Google Scholar 

  6. Moss, W.J. Measles control and the prospect of eradication. Curr. Top. Microbiol. Immunol. 330, 173–189 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  7. Smith, E.C., Popa, A., Chang, A., Masante, C. & Dutch, R.E. Viral entry mechanisms: the increasing diversity of paramyxovirus entry. FEBS J. 276, 7217–7227 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Cattaneo, R., Miest, T., Shashkova, E.V. & Barry, M.A. Reprogrammed viruses as cancer therapeutics: targeted, armed and shielded. Nat. Rev. Microbiol. 6, 529–540 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Russell, S.J. & Peng, K.-W. Measlesvirus for cancer therapy. Curr. Top. Microbiol. Immunol. 330, 213–241 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  10. Cattaneo, R. Paramyxovirus entry and targeted vectors for cancer therapy. PLoS Pathog. 6, e1000973 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  11. Navaratnarajah, C.K., Leonard, V.H.J. & Cattaneo, R. Measles virus glycoprotein complex assembly, receptor attachment and cell entry. Curr. Top. Microbiol. Immunol. 329, 59–76 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  12. Iorio, R.M., Melanson, V. & Mahon, P. Glycoprotein interactions in paramyxovirus fusion. Future Virol. 4, 335–351 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Plemper, R.K., Hammond, A. & Cattaneo, R. Characterization of a region of measles virus hemagglutinin sufficient for its dimerization. J. Virol. 74, 6485–6493 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Lee, J.K. et al. Functional interaction between paramyxovirus fusion and attachment proteins. J. Biol. Chem. 283, 16561–16572 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Brindley, M.A. & Plemper, R.K. Blue native PAGE and biomolecular complementation reveal a tetrameric or higher-order oligomer organization of the physiological measles virus attachment protein H. J. Virol. 84, 12174–12184 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Cattaneo, R. & Rose, J.K. Cell fusion by the envelope glycoproteins of persistent measles viruses which caused lethal human brain disease. J. Virol. 67, 1493–1502 (1993).

    CAS  PubMed  PubMed Central  Google Scholar 

  17. Hu, X.L., Ray, R. & Compans, R.W. Functional interactions between the fusion protein and hemagglutinin-neuraminidase of human parainfluenza viruses. J. Virol. 66, 1528–1534 (1992).

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Paal, T. et al. Probing the spatial organization of measles virus fusion complexes. J. Virol. 83, 10480–10493 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Hashiguchi, T. et al. Crystal structure of measles virus hemagglutinin provides insight into effective vaccines. Proc. Natl. Acad. Sci. USA 104, 19535–19540 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Crennell, S., Takimoto, T., Portner, A. & Taylor, G. Crystal structure of the multifunctional paramyxovirus hemagglutinin-neuraminidase. Nat. Struct. Biol. 7, 1068–1074 (2000).

    Article  CAS  PubMed  Google Scholar 

  21. Lawrence, M.C. et al. Structure of the haemagglutinin-neuraminidase from human parainfluenza virus type III. J. Mol. Biol. 335, 1343–1357 (2004).

    Article  CAS  PubMed  Google Scholar 

  22. Yuan, P. et al. Structural studies of the parainfluenza virus 5 hemagglutinin-neuraminidase tetramer in complex with its receptor, sialyllactose. Structure 13, 803–815 (2005).

    Article  CAS  PubMed  Google Scholar 

  23. Bowden, T.A., Crispin, M., Harvey, D., Jones, E.Y. & Stuard, D. Dimeric architecture of the Hendra virus attachment glycoprotein: evidence for a conserved mode of assembly. J. Virol. 84, 6208–6217 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Colf, L.A., Juo, Z.S. & Garcia, K.C. Structure of the measles virus hemagglutinin. Nat. Struct. Mol. Biol. 14, 1227–1228 (2007).

    Article  CAS  PubMed  Google Scholar 

  25. Plemper, R.K., Hammond, A.L. & Cattaneo, R. Measles virus envelope glycoproteins hetero-oligomerize in the endoplasmic reticulum. J. Biol. Chem. 276, 44239–44246 (2001).

    Article  CAS  PubMed  Google Scholar 

  26. Connolly, S.A., Leser, G.P., Jardetzky, T.S. & Lamb, R.A. Bimolecular complementation of paramyxovirus fusion and hemagglutinin-neuraminidase proteins enhances fusion: implications for the mechanism of fusion triggering. J. Virol. 83, 10857–10868 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Vongpunsawad, S., Oezgun, N., Braun, W. & Cattaneo, R. Selectively receptor-blind measles viruses: identification of residues necessary for SLAM- or CD46-induced fusion and their localization on a new hemagglutinin structural model. J. Virol. 78, 302–313 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Massé, N. et al. Measles virus (MV) hemagglutinin: evidence that attachment sites for MV receptors SLAM and CD46 overlap on the globular head. J. Virol. 78, 9051–9063 (2004).

    Article  PubMed  PubMed Central  Google Scholar 

  29. Navaratnarajah, C.K. et al. Dynamic interaction of the measles virus hemagglutinin with its receptor signaling lymphocytic activation molecule (SLAM, CD150). J. Biol. Chem. 283, 11763–11771 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Leonard, V.H.J. et al. Measles virus blind to its epithelial cell receptor remains virulent in rhesus monkeys but cannot cross the airway epithelium and is not shed. J. Clin. Invest. 118, 2448–2458 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  31. Tahara, M. et al. Measles virus infects both polarized epithelial and immune cells by using distinctive receptor-binding sites on its hemagglutinin. J. Virol. 82, 4630–4637 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Naniche, D. et al. Human membrane cofactor protein (CD46) acts as a cellular receptor for measles virus. J. Virol. 67, 6025–6032 (1993).

    CAS  PubMed  PubMed Central  Google Scholar 

  33. Dörig, R.E., Marcil, A., Chopra, A. & Richardson, C.D. The human CD46 molecule is a receptor for measles virus (Edmonston strain). Cell 75, 295–305 (1993).

    Article  PubMed  Google Scholar 

  34. Tatsuo, H., Ono, N., Tanaka, K. & Yanagi, Y. SLAM (CDw150) is a cellular receptor for measles virus. Nature 406, 893–897 (2000).

    Article  CAS  PubMed  Google Scholar 

  35. Ono, N. et al. Measles viruses on throat swabs from measles patients use signaling lymphocytic activation molecule (CDw150) but not CD46 as a cellular receptor. J. Virol. 75, 4399–4401 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Santiago, C., Celma, M.L., Stehle, T. & Casasnovas, J.M. Structure of the measles virus hemagglutinin bound to the CD46 receptor. Nat. Struct. Mol. Biol. 17, 124–129 (2010).

    Article  CAS  PubMed  Google Scholar 

  37. El Kasmi, K.C. et al. Neutralization of measles virus wild-type isolates after immunization with a synthetic peptide vaccine which is not recognized by neutralizing passive antibodies. J. Gen. Virol. 81, 729–735 (2000).

    Article  CAS  PubMed  Google Scholar 

  38. Nakamura, T. et al. Rescue and propagation of fully retargeted oncolytic measles viruses. Nat. Biotechnol. 23, 209–214 (2005).

    Article  CAS  PubMed  Google Scholar 

  39. Persson, B.D. et al. Structure of the extracellular portion of CD46 provides insights into its interactions with complement proteins and pathogens. PLoS Pathog. 6, e1001122 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  40. Devaux, P. et al. CD46 short consensus repeats III and IV enhance measles virus binding but impair soluble hemagglutinin binding. J. Virol. 71, 4157–4160 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  41. Casasnovas, J.M., Larvie, M. & Stehle, T. Crystal structure of two CD46 domains reveals an extended measles virus-binding surface. EMBO J. 18, 2911–2922 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Yuan, P., Leser, G.P., Demeler, B., Lamb, R.A. & Jardetzky, T.S. Domain architecture and oligomerization properties of the paramyxovirus PIV 5 hemagglutinin-neuraminidase (HN) protein. Virology 378, 282–291 (2008).

    Article  CAS  PubMed  Google Scholar 

  43. Buchholz, C.J., Schneider, U., Devaux, P., Gerlier, D. & Cattaneo, R. Cell entry by measles virus: long hybrid receptors uncouple binding from membrane fusion. J. Virol. 70, 3716–3723 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  44. Chen, R., Li, L. & Weng, Z. ZDOCK: an initial-stage protein-docking algorithm. Proteins 52, 80–87 (2003).

    Article  CAS  PubMed  Google Scholar 

  45. Mahon, P.J., Mirza, A.M., Musich, T.A. & Iorio, R.M. Engineered intermonomeric disulfide bonds in the globular domain of Newcastle disease virus hemagglutinin-neuraminidase protein: implications for the mechanism of fusion promotion. J. Virol. 82, 10386–10396 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Ludwig, K. et al. Electron cryomicroscopy reveals different F1 + F2 protein states in intact parainfluenza virions. J. Virol. 82, 3775–3781 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Yin, H.-S., Wen, X., Paterson, R.G., Lamb, R.A. & Jardetzky, T.S. Structure of the parainfluenza virus 5 F protein in its metastable, prefusion conformation. Nature 439, 38–44 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Ono, N., Tatsuo, H., Tanaka, K., Minagawa, H. & Yanagi, Y. V domain of human SLAM (CDw150) is essential for its function as a measles virus receptor. J. Virol. 75, 1594–1600 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Buchholz, U.J., Finke, S. & Conzelmann, K.K. Generation of bovine respiratory syncytial virus (BRSV) from cDNA: BRSV NS2 is not essential for virus replication in tissue culture, and the human RSV leader region acts as a functional BRSV genome promoter. J. Virol. 73, 251–259 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  50. Cathomen, T., Buchholz, C.J., Spielhofer, P. & Cattaneo, R. Preferential initiation at the second AUG of the measles virus F mRNA: a role for the long untranslated region. Virology 214, 628–632 (1995).

    Article  CAS  PubMed  Google Scholar 

  51. Radecke, F. et al. Rescue of measles viruses from cloned DNA. EMBO J. 14, 5773–5784 (1995).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Takeda, M. et al. Recovery of pathogenic measles virus from cloned cDNA. J. Virol. 74, 6643–6647 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Fraczkiewicz, R. & Braun, W. Exact and efficient analytical calculation of the accessible surface areas and their gradients for macromolecules. J. Comput. Chem. 19, 319–333 (1998).

    Article  CAS  Google Scholar 

  54. Cathomen, T., Naim, H.Y. & Cattaneo, R. Measles viruses with altered envelope protein cytoplasmic tails gain cell fusion competence. J. Virol. 72, 1224–1234 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

We thank J. Maher, D., Katzmann, B. Lee, C. Russell and R. Iorio for comments on the manuscript, S. Russell (Mayo Clinic) for the Vero-His cell line, C. Muller (University of Trier) for the BH6 antibody, A. Kirk (Mayo Clinic) and R. Weaver (Mayo Clinic) for help with H-tetramer interface mutagenesis, T. Stehle (University of Tuebingen) for communicating unpublished information and M. Bennett for excellent secretarial assistance. This work was supported by US National Institutes of Health grant R01 CA90636 and by the Mayo Clinic Cancer Center. Part of L.K.'s and L.R.'s stipends was supported by the Mayo Graduate School SURF program.

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Authors and Affiliations

  1. Department of Molecular Medicine, Mayo Clinic, Rochester, Minnesota, USA

    Chanakha K Navaratnarajah, Levi Rupp, Leah Kay, Vincent H J Leonard & Roberto Cattaneo

  2. Virology and Gene Therapy Track, Mayo Graduate School, Rochester, Minnesota, USA

    Chanakha K Navaratnarajah, Levi Rupp, Leah Kay, Vincent H J Leonard & Roberto Cattaneo

  3. Department of Biochemistry and Molecular Biology, University of Texas Medical Branch, Galveston, Texas, USA

    Numan Oezguen & Werner Braun

  4. Sealy Center for Structural Biology and Molecular Biophysics, University of Texas Medical Branch, Galveston, Texas, USA

    Numan Oezguen & Werner Braun

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Contributions

R.C. and C.K.N. conceived the projects. N.O. and W.B. planned cysteine mutagenesis. C.K.N. and V.H.J.L. planned histidine tagging. C.K.N., L.R. and L.K. generated the expression plasmids and characterized the function of all the mutated proteins. C.K.N., V.H.J.L., W.B. and R.C. contributed to the analysis of the data and prepared the manuscript.

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Correspondence to Roberto Cattaneo.

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Patent applications on which R.C. is an inventor have been licensed to NISCO, Inc. The Mayo Clinic has an equity position in NISCO; the Mayo Clinic has not yet received royalties from products developed by the company, but may receive these in the future.

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Navaratnarajah, C., Oezguen, N., Rupp, L. et al. The heads of the measles virus attachment protein move to transmit the fusion-triggering signal. Nat Struct Mol Biol 18, 128–134 (2011). https://doi.org/10.1038/nsmb.1967

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