Receptor Specificity and Receptor-Induced Conformational Changes in Mouse Hepatitis Virus Spike Glycoprotein

  • Kathryn V. Holmes
  • Bruce D. Zelus
  • Jeanne H. Schickli
  • Susan R. Weiss
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 494)


Coronavirus spike (S) glycoproteins bind to specific glycoproteins on host cell membranes that serve as virus receptors. Receptors for S glycoproteins of several coronaviruses have been identified (Dveksler, et al, 1991; Dveksler, et al, 1993; Chen, et al, 1995; Yeager, et al, 1992; Delmas, et al, 1992; Tresnan, et al, 1996; Benbacer, et al, 1997). The specificity of virus/receptor interactions is an important determinant of the species-specificity of Coronavirus infection, and may play a role in the tissue tropism and virulence of Coronavirus diseases (Kolb, et al, 1997; Ballesteros, et al, 1997; Sanchez, et al, 1999). The mechanism of entry has been studied in great detail for several enveloped viruses including influenza A virus, avian leukosis viruses and HIV-1 (Kemble, et al, 1994; Stegmann, et al, 1990; Chen, et al, 1999; Gilbert, et al, 1995; Hernandez and White, 1998; Zhang, et al, 1999; Turner and Summers, 1999). Binding of the spike glycoprotein on the viral envelope to the receptor on the cell membrane may induce specific, pre-programmed conformational changes in the spike protein and/or the receptor that bring together the lipid bilayers of the viral envelope and the cell membrane. A fusion pore is created that expands to permit the entry of the viral nucleocapsid into the cytoplasm, leading to virus infection. This chapter will summarize the specificity of the interactions of murine Coronavirus MHV and mutants of MHV with cellular receptors, and discuss evidence that receptor binding induces a temperature-dependent conformational change in the MHV S glycoprotein that may play a role in virus entry and MHV-induced cell fusion.


Soluble Receptor Mouse Hepatitis Virus Spike Protein Avian Leukosis Virus Feline Infectious Peritonitis 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


  1. Ballesteros, M. L., C. M. Sanchez, and L. Enjuanes. 1997. Two amino acid changes at the N-terminus of transmissible gastroenteritis Coronavirus spike protein result in the loss of enteric tropism. Virology. 227:378–388.PubMedCrossRefGoogle Scholar
  2. Baric, R. S., B. Yount, L. Hensley, S. A. Peel, and W. Chen. 1997. Episodic evolution mediates interspecies transfer of a murine Coronavirus. J. Virol. 71:1946–1955.PubMedGoogle Scholar
  3. Baric, R. S., E. Sullivan, L. Hensley, B. Yount, and W. Chen. 1999. Persistent infection promotes cross-species transmissibility of mouse hepatitis virus. J. Virol. 73:638–649.PubMedGoogle Scholar
  4. Beauchemin, N., T. Chen, P. Draber, G. Dveksler, P. Gold, S. Gray-Owen, F. Grunert, S. Hammarstrom, K. V. Holmes, A. Karlson, M. Kuroki, S. H. Lin, L. Lucka, S. M. Najjar, M. Neumaier, B. Obrink, J. E. Shively, K. M. Skubitz, C. P. Stanners, P. Thomas, J. A. Thompson, M. Virji, S. von Kleist, C. Wagener, S. Watt, and W. Zimmermann. 1999. Redefined nomenclature for members of the carcinoembryonic antigen family. Exp. Cell Res. 252:243–249.PubMedCrossRefGoogle Scholar
  5. Benbacer, L., E. Kut, L. Besnardeau, H. Laude, and B. Delmas. 1997. Interspecies aminopeptidase-N chimeras reveal species-specific receptor recognition by canine Coronavirus, feline infectious peritonitis virus, and transmissible gastroenteritis virus. J.Virol. 71:734–737.PubMedGoogle Scholar
  6. Chen, D. S., M. Asanaka, K. Yokomori, F. Wang, S. B. Hwang, H. P. Li, and M. M. Lai. 1995. A pregnancy-specific glycoprotein is expressed in the brain and serves as a receptor for mouse hepatitis virus. Proc. Natl. Acad. Sci U. S. A. 92:12095–12099.PubMedCrossRefGoogle Scholar
  7. Chen, J., J. J. Skehel, and D. C. Wiley. 1999. N-and C-terminal residues combine in the fusion-pH influenza hemagglutinin HA(2) subunit to form an N cap that terminates the triple-stranded coiled coil. Proc. Natl. Acad. Sci U. S. A. 96:8967–8972.PubMedCrossRefGoogle Scholar
  8. Chen, W. and R. S. Baric. 1996. Molecular anatomy of mouse hepatitis virus persistence: coevolution of increased host cell resistance and virus virulence. J. Virol. 70:3947–3960.PubMedGoogle Scholar
  9. Coutelier, J. P., C. Godfraind, G. S. Dveksler, M. Wysocka, C. B. Cardellichio, H. Noel, and K. V. Holmes. 1994. B lymphocyte and macrophage expression of carcinoembryonic antigen-related adhesion molecules that serve as receptors for murine Coronavirus. Eur. J. Immunol. 24:1383–1390.PubMedCrossRefGoogle Scholar
  10. Delmas, B., J. Gelfi, R. L’Haridon, L. K. Vogel, H. Sjostrom, O. Noren, and H. Laude. 1992. Aminopeptidase N is a major receptor for the entero-pathogenic Coronavirus TGEV. Nature 357:417–420.PubMedCrossRefGoogle Scholar
  11. Dveksler, G. S., M. N. Pensiero, C. B. Cardellichio, R. K. Williams, G. S. Jiang, K. V. Holmes, and C. W. Dieffenbach. 1991. Cloning of the mouse hepatitis virus (MHV) receptor: expression in human and hamster cell lines confers susceptibility to MHV. J. Virol. 65:6881–6891.PubMedGoogle Scholar
  12. Dveksler, G. S., C. W. Dieffenbach, C. B. Cardellichio, K. McCuaig, M. N. Pensiero, G. S. Jiang, N. Beauchemin, and K. V. Holmes. 1993. Several members of the mouse carcinoembryonic antigen-related glycoprotein family are functional receptors for the Coronavirus mouse hepatitis virus-A59. J. Virol. 67:1–8.PubMedGoogle Scholar
  13. Frana, M. F., J. N. Behnke, L. S. Sturman, and K. V. Holmes. 1985. Proteolytic cleavage of the E2 glycoprotein of murine Coronavirus: host-dependent differences in proteolytic cleavage and cell fusion. J. Virol. 56:912–920.PubMedGoogle Scholar
  14. Gallagher, T. M. 1991. Alteration of the pH dependence of coronavirus-induced cell fusion: effect of mutations in the spike glycoprotein. J. Virol. 65:1916–2128.PubMedGoogle Scholar
  15. Gilbert, J. M., L. D. Hernandez, J. W. Balliet, P. Bates, and J. M. White. 1995. Receptor-induced conformational changes in the subgroup A avian leukosis and sarcoma virus envelope glycoprotein. J. Virol. 69:7410–7415.PubMedGoogle Scholar
  16. Godfraind, C., S. G. Langreth, C. B. Cardellichio, R. Knobler, J. P. Coutelier, M. Dubois-Dalcq, and K. V. Holmes. 1995. Tissue and cellular distribution of an adhesion molecule in the carcinoembryonic antigen family that serves as a receptor for mouse hepatitis virus. Lab. Invest. 73:615–627.PubMedGoogle Scholar
  17. Gombold, J. L., S. T. Hingley, and S. R. Weiss. 1993. Fusion-defective mutants of mouse hepatitis virus A59 contain a mutation in the spike protein cleavage signal. J. Virol. 67:4504–4512.PubMedGoogle Scholar
  18. Hernandez, L. D. and J. M. White. 1998. Mutational analysis of the candidate internal fusion peptide of the avian leukosis and sarcoma virus subgroup A envelope glycoprotein. J. Virol. 72:3259–3267.PubMedGoogle Scholar
  19. Holmes, K. V. and J. N. Behnke. 1981. Evolution of a Coronavirus during persistent infection in vitro. Adv Exp Med Biol 142:287–299.PubMedGoogle Scholar
  20. Huber, M., L. Izzi, P. Grondin, C. Houde, T. Kunath, A. Veillette, and N. Beauchemin. 1999. The carboxyl-terminal region of biliary glycoprotein controls its tyrosine phosphorylation and association with protein-tyrosine phosphatases SHP-1 and SHP-2 in epithelial cells. J. Biol Chem. 274:335–344.PubMedCrossRefGoogle Scholar
  21. Kemble, G. W., T. Danieli, and J. M. White. 1994. Lipid-anchored influenza hemagglutinin promotes hemifusion, not complete fusion. Cell 76:383–391.PubMedCrossRefGoogle Scholar
  22. Kolb, A. F., A. Hegyi, and S. G. Siddell. 1997. Identification of residues critical for the human Coronavirus 229E receptor function of human aminopeptidase N. J. Gen. Virol. 78:2795–2802.PubMedGoogle Scholar
  23. Kubo, H., Y. K. Yamada, and F. Taguchi. 1994. Localization of neutralizing epitopes and the receptor-binding site within the amino-terminal 330 amino acids of the murine Coronavirus spike protein. J. Virol. 68:5403–5410.PubMedGoogle Scholar
  24. Kuo, L., G. J. Godeke, M. J. Raamsman, P. S. Masters, and P. J. Rottier. 2000. Retargeting of Coronavirus by substitution of the spike glycoprotein ectodomain: crossing the host cell species barrier. J. Virol. 2000. Feb;74(3): 1393–1406. 74:1393-1406.PubMedCrossRefGoogle Scholar
  25. Lavi, E., A. Suzumura, M. Hirayama, M. K. Highkin, D. M. Dambach, D. H. Silberberg, and S. R. Weiss. 1987. Coronavirus mouse hepatitis virus (MHV)-A59 causes a persistent, productive infection in primary glial cell cultures. Microb. Pathog. 3:79–86.PubMedCrossRefGoogle Scholar
  26. Nedellec, P., C. Turbide, and N. Beauchemin. 1995. Characterization and transactional activity of the mouse biliary glycoprotein 1 gene, a carcinoembryonic antigen-related gene. Eur. J. Biochem. 231:104–114.PubMedCrossRefGoogle Scholar
  27. Sanchez, C. M., A. Izeta, J. M. Sanchez-Morgado, S. Alonso, I. Sola, M. Balasch, J. Plana-Duran, and L. Enjuanes. 1999. Targeted recombination demonstrates that the spike gene of transmissible gastroenteritis Coronavirus is a determinant of its enteric tropism and virulence. J. Virol. 73:7607–7618.PubMedGoogle Scholar
  28. Sawicki, S. G., J. H. Lu, and K. V. Holmes. 1995. Persistent infection of cultured cells with mouse hepatitis virus (MHV) results from the epigenetic expression of the MHV receptor. Journal of Virology 69:5535–5543.PubMedGoogle Scholar
  29. Schickli, J. H., B. D. Zelus, D. E. Wentworth, S. G. Sawicki, and K. V. Holmes. 1997. The murine Coronavirus mouse hepatitis virus strain A59 from persistently infected murine cells exhibits an extended host range. J. Virol. 71:9499–9507.PubMedGoogle Scholar
  30. Stegmann, T., J. M. White, and A. Helenius. 1990. Intermediates in influenza induced membrane fusion. EMBO J. 9:4231–4241.PubMedGoogle Scholar
  31. Sturman, L. S. and K. V. Holmes. 1977. Characterization of Coronavirus II. Glycoproteins of the viral envelope: tryptic peptide analysis. Virology. 77:650–660.PubMedCrossRefGoogle Scholar
  32. Sturman, L. S., C. S. Ricard, and K. V. Holmes. 1990. Conformational change of the Coronavirus peplomer glycoprotein at pH 8.0 and 37 degrees C correlates with virus aggregation and virus-induced cell fusion. J. Virol. 64:3042–3050.PubMedGoogle Scholar
  33. Tresnan, D. B., R. Levis, and K. V. Holmes. 1996. Feline aminopeptidase N serves as a receptor for feline, canine, porcine, and human coronaviruses in serogroup I. J. Virol. 70:8669–8674.PubMedGoogle Scholar
  34. Turbide, C., M. Rojas, C. P. Stanners, and N. Beauchemin. 1991. A mouse carcinoembryonic antigen gene family member is a calcium-dependent cell adhesion molecule. J. Biol Chem. 266:309–315.PubMedGoogle Scholar
  35. Turner, B. G. and M. F. Summers. 1999. Structural biology of HIV. J. Mol. Biol 285:1–32.PubMedCrossRefGoogle Scholar
  36. Virji, M., D. Evans, A. Hadfield, F. Grunert, A. M. Teixeira, and S. M. Watt. 1999. Critical determinants of host receptor targeting by Neisseria meningitidis and Neisseria gonorrhoeae: identification of Opa adhesiotopes on the N-domain of CD66 molecules. Mol. Microbiol. 34:538–551.PubMedCrossRefGoogle Scholar
  37. Virji, M., D. Evans, J. Griffith, D. Hill, L. Serino, A. Hadfield, and S. M. Watt. 2000. Carcinoembryonic antigens are targeted by diverse strains of typable and non-typable Haemophilus influenzae. Mol. Microbiol. 2000. May;36(4):784–795. 36:784-795.PubMedCrossRefGoogle Scholar
  38. Weismiller, D. G., L. S. Sturman, M. J. Buchmeier, J. O. Fleming, and K. V. Holmes. 1990. Monoclonal antibodies to the peplomer glycoprotein of Coronavirus mouse hepatitis virus identify two subunits and detect a conformational change in the subunit released under mild alkaline conditions. J. Virol. 64:3051–3055.PubMedGoogle Scholar
  39. Yeager, C. L., R. A. Ashmun, R. K. Williams, C. B. Cardellichio, L. H. Shapiro, A. T. Look, and K. V. Holmes. 1992. Human aminopeptidase N is a receptor for human Coronavirus 229E. Nature. 357:420–422.PubMedCrossRefGoogle Scholar
  40. Yokomori, K. and M. M. Lai. 1992. The receptor for mouse hepatitis virus in the resistant mouse strain SJL is functional: implications for the requirement of a second factor for viral infection. J. Virol. 66:6931–6938.PubMedGoogle Scholar
  41. Zelus, B. D., D. R. Wessner, R. K. Williams, M. N. Pensiero, F. T. Phibbs, M. deSouza, G. S. Dveksler, and K. V. Holmes. 1998. Purified, soluble recombinant mouse hepatitis virus receptor, Bgpl(b), and Bgp2 murine Coronavirus receptors differ in mouse hepatitis virus binding and neutralizing activities. J. Virol. 72:7237–7244.PubMedGoogle Scholar
  42. Zhang, W., G. Canziani, C. Plugariu, R. Wyatt, J. Sodroski, R. Sweet, P. Kwong, W. Hendrickson, and I. Chaiken. 1999. Conformational changes of gpl20 in epitopes near the CCR5 binding site are induced by CD4 and a CD4 miniprotein mimetic. Biochemistry 38:9405–9416.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2001

Authors and Affiliations

  • Kathryn V. Holmes
    • 1
  • Bruce D. Zelus
    • 1
  • Jeanne H. Schickli
    • 1
  • Susan R. Weiss
    • 2
  1. 1.University of Colorado Health Sciences CenterDenverUSA
  2. 2.University of Pennsylvania School of MedicinePhiladelphiaUSA

Personalised recommendations