Skip to main content
The EMBO Journal logoLink to The EMBO Journal
. 1999 Feb 1;18(3):543–554. doi: 10.1093/emboj/18.3.543

The structure and function of a foot-and-mouth disease virus-oligosaccharide receptor complex.

E E Fry 1, S M Lea 1, T Jackson 1, J W Newman 1, F M Ellard 1, W E Blakemore 1, R Abu-Ghazaleh 1, A Samuel 1, A M King 1, D I Stuart 1
PMCID: PMC1171147  PMID: 9927414

Abstract

Heparan sulfate has an important role in cell entry by foot-and-mouth disease virus (FMDV). We find that subtype O1 FMDV binds this glycosaminoglycan with a high affinity by immobilizing a specific highly abundant motif of sulfated sugars. The binding site is a shallow depression on the virion surface, located at the junction of the three major capsid proteins, VP1, VP2 and VP3. Two pre-formed sulfate-binding sites control receptor specificity. Residue 56 of VP3, an arginine in this virus, is critical to this recognition, forming a key component of both sites. This residue is a histidine in field isolates of the virus, switching to an arginine in adaptation to tissue culture, forming the high affinity heparan sulfate-binding site. We postulate that this site is a conserved feature of FMDVs, such that in the infected animal there is a biological advantage to low affinity, or more selective, interactions with glycosaminoglycan receptors.

Full Text

The Full Text of this article is available as a PDF (759.3 KB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Acharya R., Fry E., Stuart D., Fox G., Rowlands D., Brown F. The three-dimensional structure of foot-and-mouth disease virus at 2.9 A resolution. Nature. 1989 Feb 23;337(6209):709–716. doi: 10.1038/337709a0. [DOI] [PubMed] [Google Scholar]
  2. Bauer P. H., Bronson R. T., Fung S. C., Freund R., Stehle T., Harrison S. C., Benjamin T. L. Genetic and structural analysis of a virulence determinant in polyomavirus VP1. J Virol. 1995 Dec;69(12):7925–7931. doi: 10.1128/jvi.69.12.7925-7931.1995. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Baxt B., Becker Y. The effect of peptides containing the arginine-glycine-aspartic acid sequence on the adsorption of foot-and-mouth disease virus to tissue culture cells. Virus Genes. 1990 Jun;4(1):73–83. doi: 10.1007/BF00308567. [DOI] [PubMed] [Google Scholar]
  4. Berinstein A., Roivainen M., Hovi T., Mason P. W., Baxt B. Antibodies to the vitronectin receptor (integrin alpha V beta 3) inhibit binding and infection of foot-and-mouth disease virus to cultured cells. J Virol. 1995 Apr;69(4):2664–2666. doi: 10.1128/jvi.69.4.2664-2666.1995. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Carrillo E. C., Giachetti C., Campos R. H. Effect of lysosomotropic agents on the foot-and-mouth disease virus replication. Virology. 1984 Jun;135(2):542–545. doi: 10.1016/0042-6822(84)90208-3. [DOI] [PubMed] [Google Scholar]
  6. Casset F., Hamelryck T., Loris R., Brisson J. R., Tellier C., Dao-Thi M. H., Wyns L., Poortmans F., Pérez S., Imberty A. NMR, molecular modeling, and crystallographic studies of lentil lectin-sucrose interaction. J Biol Chem. 1995 Oct 27;270(43):25619–25628. doi: 10.1074/jbc.270.43.25619. [DOI] [PubMed] [Google Scholar]
  7. Casu B., Petitou M., Provasoli M., Sinaÿ P. Conformational flexibility: a new concept for explaining binding and biological properties of iduronic acid-containing glycosaminoglycans. Trends Biochem Sci. 1988 Jun;13(6):221–225. doi: 10.1016/0968-0004(88)90088-6. [DOI] [PubMed] [Google Scholar]
  8. Clapham P. R., Weiss R. A. Immunodeficiency viruses. Spoilt for choice of co-receptors. Nature. 1997 Jul 17;388(6639):230–231. doi: 10.1038/40758. [DOI] [PubMed] [Google Scholar]
  9. Compton T., Nowlin D. M., Cooper N. R. Initiation of human cytomegalovirus infection requires initial interaction with cell surface heparan sulfate. Virology. 1993 Apr;193(2):834–841. doi: 10.1006/viro.1993.1192. [DOI] [PubMed] [Google Scholar]
  10. Crowther J. R., Farias S., Carpenter W. C., Samuel A. R. Identification of a fifth neutralizable site on type O foot-and-mouth disease virus following characterization of single and quintuple monoclonal antibody escape mutants. J Gen Virol. 1993 Aug;74(Pt 8):1547–1553. doi: 10.1099/0022-1317-74-8-1547. [DOI] [PubMed] [Google Scholar]
  11. Curry S., Abrams C. C., Fry E., Crowther J. C., Belsham G. J., Stuart D. I., King A. M. Viral RNA modulates the acid sensitivity of foot-and-mouth disease virus capsids. J Virol. 1995 Jan;69(1):430–438. doi: 10.1128/jvi.69.1.430-438.1995. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Curry S., Abu-Ghazaleh R., Blakemore W., Fry E., Jackson T., King A., Lea S., Logan D., Newman J., Stuart D. Crystallization and preliminary X-ray analysis of three serotypes of foot-and-mouth disease virus. J Mol Biol. 1992 Dec 20;228(4):1263–1268. doi: 10.1016/0022-2836(92)90332-e. [DOI] [PubMed] [Google Scholar]
  13. Curry S., Fry E., Blakemore W., Abu-Ghazaleh R., Jackson T., King A., Lea S., Newman J., Rowlands D., Stuart D. Perturbations in the surface structure of A22 Iraq foot-and-mouth disease virus accompanying coupled changes in host cell specificity and antigenicity. Structure. 1996 Feb 15;4(2):135–145. doi: 10.1016/s0969-2126(96)00017-2. [DOI] [PubMed] [Google Scholar]
  14. Esko J. D., Weinke J. L., Taylor W. H., Ekborg G., Rodén L., Anantharamaiah G., Gawish A. Inhibition of chondroitin and heparan sulfate biosynthesis in Chinese hamster ovary cell mutants defective in galactosyltransferase I. J Biol Chem. 1987 Sep 5;262(25):12189–12195. [PubMed] [Google Scholar]
  15. Esnouf R. M. An extensively modified version of MolScript that includes greatly enhanced coloring capabilities. J Mol Graph Model. 1997 Apr;15(2):132-4, 112-3. doi: 10.1016/S1093-3263(97)00021-1. [DOI] [PubMed] [Google Scholar]
  16. Faham S., Hileman R. E., Fromm J. R., Linhardt R. J., Rees D. C. Heparin structure and interactions with basic fibroblast growth factor. Science. 1996 Feb 23;271(5252):1116–1120. doi: 10.1126/science.271.5252.1116. [DOI] [PubMed] [Google Scholar]
  17. Felding-Habermann B., Cheresh D. A. Vitronectin and its receptors. Curr Opin Cell Biol. 1993 Oct;5(5):864–868. doi: 10.1016/0955-0674(93)90036-p. [DOI] [PubMed] [Google Scholar]
  18. Feng Y., Broder C. C., Kennedy P. E., Berger E. A. HIV-1 entry cofactor: functional cDNA cloning of a seven-transmembrane, G protein-coupled receptor. Science. 1996 May 10;272(5263):872–877. doi: 10.1126/science.272.5263.872. [DOI] [PubMed] [Google Scholar]
  19. Fox G., Parry N. R., Barnett P. V., McGinn B., Rowlands D. J., Brown F. The cell attachment site on foot-and-mouth disease virus includes the amino acid sequence RGD (arginine-glycine-aspartic acid). J Gen Virol. 1989 Mar;70(Pt 3):625–637. doi: 10.1099/0022-1317-70-3-625. [DOI] [PubMed] [Google Scholar]
  20. Fox G., Stuart D., Acharya K. R., Fry E., Rowlands D., Brown F. Crystallization and preliminary X-ray diffraction analysis of foot-and-mouth disease virus. J Mol Biol. 1987 Aug 5;196(3):591–597. doi: 10.1016/0022-2836(87)90035-0. [DOI] [PubMed] [Google Scholar]
  21. Freund R., Calderone A., Dawe C. J., Benjamin T. L. Polyomavirus tumor induction in mice: effects of polymorphisms of VP1 and large T antigen. J Virol. 1991 Jan;65(1):335–341. doi: 10.1128/jvi.65.1.335-341.1991. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Gubareva L. V., Penn C. R., Webster R. G. Inhibition of replication of avian influenza viruses by the neuraminidase inhibitor 4-guanidino-2,4-dideoxy-2,3-dehydro-N-acetylneuraminic acid. Virology. 1995 Oct 1;212(2):323–330. doi: 10.1006/viro.1995.1489. [DOI] [PubMed] [Google Scholar]
  23. Haydon D., Lea S., Fry L., Knowles N., Samuel A. R., Stuart D., Woolhouse M. E. Characterizing sequence variation in the VP1 capsid proteins of foot and mouth disease virus (serotype 0) with respect to virion structure. J Mol Evol. 1998 Apr;46(4):465–475. doi: 10.1007/pl00006327. [DOI] [PubMed] [Google Scholar]
  24. Iozzo R. V. Turnover of heparan sulfate proteoglycan in human colon carcinoma cells. A quantitative biochemical and autoradiographic study. J Biol Chem. 1987 Feb 5;262(4):1888–1900. [PubMed] [Google Scholar]
  25. Jackson T., Ellard F. M., Ghazaleh R. A., Brookes S. M., Blakemore W. E., Corteyn A. H., Stuart D. I., Newman J. W., King A. M. Efficient infection of cells in culture by type O foot-and-mouth disease virus requires binding to cell surface heparan sulfate. J Virol. 1996 Aug;70(8):5282–5287. doi: 10.1128/jvi.70.8.5282-5287.1996. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Jackson T., Sharma A., Ghazaleh R. A., Blakemore W. E., Ellard F. M., Simmons D. L., Newman J. W., Stuart D. I., King A. M. Arginine-glycine-aspartic acid-specific binding by foot-and-mouth disease viruses to the purified integrin alpha(v)beta3 in vitro. J Virol. 1997 Nov;71(11):8357–8361. doi: 10.1128/jvi.71.11.8357-8361.1997. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Jarousse N., Grant R. A., Hogle J. M., Zhang L., Senkowski A., Roos R. P., Michiels T., Brahic M., McAllister A. A single amino acid change determines persistence of a chimeric Theiler's virus. J Virol. 1994 May;68(5):3364–3368. doi: 10.1128/jvi.68.5.3364-3368.1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Jarousse N., Martinat C., Syan S., Brahic M., McAllister A. Role of VP2 amino acid 141 in tropism of Theiler's virus within the central nervous system. J Virol. 1996 Nov;70(11):8213–8217. doi: 10.1128/jvi.70.11.8213-8217.1996. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Jones T. A. Diffraction methods for biological macromolecules. Interactive computer graphics: FRODO. Methods Enzymol. 1985;115:157–171. doi: 10.1016/0076-6879(85)15014-7. [DOI] [PubMed] [Google Scholar]
  30. Kitson J. D., McCahon D., Belsham G. J. Sequence analysis of monoclonal antibody resistant mutants of type O foot and mouth disease virus: evidence for the involvement of the three surface exposed capsid proteins in four antigenic sites. Virology. 1990 Nov;179(1):26–34. doi: 10.1016/0042-6822(90)90269-w. [DOI] [PubMed] [Google Scholar]
  31. Kost C., Stüber W., Ehrlich H. J., Pannekoek H., Preissner K. T. Mapping of binding sites for heparin, plasminogen activator inhibitor-1, and plasminogen to vitronectin's heparin-binding region reveals a novel vitronectin-dependent feedback mechanism for the control of plasmin formation. J Biol Chem. 1992 Jun 15;267(17):12098–12105. [PubMed] [Google Scholar]
  32. Lea S., Abu-Ghazaleh R., Blakemore W., Curry S., Fry E., Jackson T., King A., Logan D., Newman J., Stuart D. Structural comparison of two strains of foot-and-mouth disease virus subtype O1 and a laboratory antigenic variant, G67. Structure. 1995 Jun 15;3(6):571–580. doi: 10.1016/s0969-2126(01)00191-5. [DOI] [PubMed] [Google Scholar]
  33. Lea S., Hernández J., Blakemore W., Brocchi E., Curry S., Domingo E., Fry E., Abu-Ghazaleh R., King A., Newman J. The structure and antigenicity of a type C foot-and-mouth disease virus. Structure. 1994 Feb 15;2(2):123–139. doi: 10.1016/s0969-2126(00)00014-9. [DOI] [PubMed] [Google Scholar]
  34. Logan D., Abu-Ghazaleh R., Blakemore W., Curry S., Jackson T., King A., Lea S., Lewis R., Newman J., Parry N. Structure of a major immunogenic site on foot-and-mouth disease virus. Nature. 1993 Apr 8;362(6420):566–568. doi: 10.1038/362566a0. [DOI] [PubMed] [Google Scholar]
  35. Luo M., Vriend G., Kamer G., Minor I., Arnold E., Rossmann M. G., Boege U., Scraba D. G., Duke G. M., Palmenberg A. C. The atomic structure of Mengo virus at 3.0 A resolution. Science. 1987 Jan 9;235(4785):182–191. doi: 10.1126/science.3026048. [DOI] [PubMed] [Google Scholar]
  36. Martínez M. A., Verdaguer N., Mateu M. G., Domingo E. Evolution subverting essentiality: dispensability of the cell attachment Arg-Gly-Asp motif in multiply passaged foot-and-mouth disease virus. Proc Natl Acad Sci U S A. 1997 Jun 24;94(13):6798–6802. doi: 10.1073/pnas.94.13.6798. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Mason P. W., Rieder E., Baxt B. RGD sequence of foot-and-mouth disease virus is essential for infecting cells via the natural receptor but can be bypassed by an antibody-dependent enhancement pathway. Proc Natl Acad Sci U S A. 1994 Mar 1;91(5):1932–1936. doi: 10.1073/pnas.91.5.1932. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Merritt E. A., Murphy M. E. Raster3D Version 2.0. A program for photorealistic molecular graphics. Acta Crystallogr D Biol Crystallogr. 1994 Nov 1;50(Pt 6):869–873. doi: 10.1107/S0907444994006396. [DOI] [PubMed] [Google Scholar]
  39. Mettenleiter T. C., Zsak L., Zuckermann F., Sugg N., Kern H., Ben-Porat T. Interaction of glycoprotein gIII with a cellular heparinlike substance mediates adsorption of pseudorabies virus. J Virol. 1990 Jan;64(1):278–286. doi: 10.1128/jvi.64.1.278-286.1990. [DOI] [PMC free article] [PubMed] [Google Scholar]
  40. Neff S., Sá-Carvalho D., Rieder E., Mason P. W., Blystone S. D., Brown E. J., Baxt B. Foot-and-mouth disease virus virulent for cattle utilizes the integrin alpha(v)beta3 as its receptor. J Virol. 1998 May;72(5):3587–3594. doi: 10.1128/jvi.72.5.3587-3594.1998. [DOI] [PMC free article] [PubMed] [Google Scholar]
  41. Nicholls A., Sharp K. A., Honig B. Protein folding and association: insights from the interfacial and thermodynamic properties of hydrocarbons. Proteins. 1991;11(4):281–296. doi: 10.1002/prot.340110407. [DOI] [PubMed] [Google Scholar]
  42. Olson N. H., Kolatkar P. R., Oliveira M. A., Cheng R. H., Greve J. M., McClelland A., Baker T. S., Rossmann M. G. Structure of a human rhinovirus complexed with its receptor molecule. Proc Natl Acad Sci U S A. 1993 Jan 15;90(2):507–511. doi: 10.1073/pnas.90.2.507. [DOI] [PMC free article] [PubMed] [Google Scholar]
  43. Palese P., Tobita K., Ueda M., Compans R. W. Characterization of temperature sensitive influenza virus mutants defective in neuraminidase. Virology. 1974 Oct;61(2):397–410. doi: 10.1016/0042-6822(74)90276-1. [DOI] [PubMed] [Google Scholar]
  44. Parry N., Fox G., Rowlands D., Brown F., Fry E., Acharya R., Logan D., Stuart D. Structural and serological evidence for a novel mechanism of antigenic variation in foot-and-mouth disease virus. Nature. 1990 Oct 11;347(6293):569–572. doi: 10.1038/347569a0. [DOI] [PubMed] [Google Scholar]
  45. Potts J. R., Campbell I. D. Fibronectin structure and assembly. Curr Opin Cell Biol. 1994 Oct;6(5):648–655. doi: 10.1016/0955-0674(94)90090-6. [DOI] [PubMed] [Google Scholar]
  46. Rossmann M. G., Arnold E., Erickson J. W., Frankenberger E. A., Griffith J. P., Hecht H. J., Johnson J. E., Kamer G., Luo M., Mosser A. G. Structure of a human common cold virus and functional relationship to other picornaviruses. Nature. 1985 Sep 12;317(6033):145–153. doi: 10.1038/317145a0. [DOI] [PubMed] [Google Scholar]
  47. Sa-Carvalho D., Rieder E., Baxt B., Rodarte R., Tanuri A., Mason P. W. Tissue culture adaptation of foot-and-mouth disease virus selects viruses that bind to heparin and are attenuated in cattle. J Virol. 1997 Jul;71(7):5115–5123. doi: 10.1128/jvi.71.7.5115-5123.1997. [DOI] [PMC free article] [PubMed] [Google Scholar]
  48. Salmivirta M., Lidholt K., Lindahl U. Heparan sulfate: a piece of information. FASEB J. 1996 Sep;10(11):1270–1279. doi: 10.1096/fasebj.10.11.8836040. [DOI] [PubMed] [Google Scholar]
  49. Sekiguchi K., Franke A. J., Baxt B. Competition for cellular receptor sites among selected aphthoviruses. Arch Virol. 1982;74(1):53–64. doi: 10.1007/BF01320782. [DOI] [PubMed] [Google Scholar]
  50. Stehle T., Harrison S. C. Crystal structures of murine polyomavirus in complex with straight-chain and branched-chain sialyloligosaccharide receptor fragments. Structure. 1996 Feb 15;4(2):183–194. doi: 10.1016/s0969-2126(96)00021-4. [DOI] [PubMed] [Google Scholar]
  51. Stehle T., Yan Y., Benjamin T. L., Harrison S. C. Structure of murine polyomavirus complexed with an oligosaccharide receptor fragment. Nature. 1994 May 12;369(6476):160–163. doi: 10.1038/369160a0. [DOI] [PubMed] [Google Scholar]
  52. Stuart D. I., Levine M., Muirhead H., Stammers D. K. Crystal structure of cat muscle pyruvate kinase at a resolution of 2.6 A. J Mol Biol. 1979 Oct 15;134(1):109–142. doi: 10.1016/0022-2836(79)90416-9. [DOI] [PubMed] [Google Scholar]
  53. Surovoi A. Iu, Ivanov V. T., Chepurkin A. V., Ivaniushchenkov V. N., Driagalin N. N. Iavliaetsia li posledovatel'nost' Arg-Gly-Asp uchastkom sviazyvaniia virusa iashchura s kletochnym retseptorom? Bioorg Khim. 1988 Jul;14(7):965–968. [PubMed] [Google Scholar]
  54. Wagner L., Yang O. O., Garcia-Zepeda E. A., Ge Y., Kalams S. A., Walker B. D., Pasternack M. S., Luster A. D. Beta-chemokines are released from HIV-1-specific cytolytic T-cell granules complexed to proteoglycans. Nature. 1998 Feb 26;391(6670):908–911. doi: 10.1038/36129. [DOI] [PubMed] [Google Scholar]
  55. Wallace A. C., Laskowski R. A., Thornton J. M. LIGPLOT: a program to generate schematic diagrams of protein-ligand interactions. Protein Eng. 1995 Feb;8(2):127–134. doi: 10.1093/protein/8.2.127. [DOI] [PubMed] [Google Scholar]
  56. Weis W., Brown J. H., Cusack S., Paulson J. C., Skehel J. J., Wiley D. C. Structure of the influenza virus haemagglutinin complexed with its receptor, sialic acid. Nature. 1988 Jun 2;333(6172):426–431. doi: 10.1038/333426a0. [DOI] [PubMed] [Google Scholar]
  57. Wickham T. J., Mathias P., Cheresh D. A., Nemerow G. R. Integrins alpha v beta 3 and alpha v beta 5 promote adenovirus internalization but not virus attachment. Cell. 1993 Apr 23;73(2):309–319. doi: 10.1016/0092-8674(93)90231-e. [DOI] [PubMed] [Google Scholar]
  58. WuDunn D., Spear P. G. Initial interaction of herpes simplex virus with cells is binding to heparan sulfate. J Virol. 1989 Jan;63(1):52–58. doi: 10.1128/jvi.63.1.52-58.1989. [DOI] [PMC free article] [PubMed] [Google Scholar]
  59. Wu L., Gerard N. P., Wyatt R., Choe H., Parolin C., Ruffing N., Borsetti A., Cardoso A. A., Desjardin E., Newman W. CD4-induced interaction of primary HIV-1 gp120 glycoproteins with the chemokine receptor CCR-5. Nature. 1996 Nov 14;384(6605):179–183. doi: 10.1038/384179a0. [DOI] [PubMed] [Google Scholar]
  60. Xie Q. C., McCahon D., Crowther J. R., Belsham G. J., McCullough K. C. Neutralization of foot-and-mouth disease virus can be mediated through any of at least three separate antigenic sites. J Gen Virol. 1987 Jun;68(Pt 6):1637–1647. doi: 10.1099/0022-1317-68-6-1637. [DOI] [PubMed] [Google Scholar]
  61. Yanagishita M., Hascall V. C. Metabolism of proteoglycans in rat ovarian granulosa cell culture. Multiple intracellular degradative pathways and the effect of chloroquine. J Biol Chem. 1984 Aug 25;259(16):10270–10283. [PubMed] [Google Scholar]
  62. Zhou L., Lin X., Green T. J., Lipton H. L., Luo M. Role of sialyloligosaccharide binding in Theiler's virus persistence. J Virol. 1997 Dec;71(12):9701–9712. doi: 10.1128/jvi.71.12.9701-9712.1997. [DOI] [PMC free article] [PubMed] [Google Scholar]

Articles from The EMBO Journal are provided here courtesy of Nature Publishing Group

RESOURCES