Skip to main content
NCBI home page
Biochemical Journal logoLink to Biochemical Journal
. 2000 Oct 1;351(Pt 1):79–86. doi: 10.1042/0264-6021:3510079

The second domain of intercellular adhesion molecule-1 (ICAM-1) maintains the structural integrity of the leucocyte function-associated antigen-1 (LFA-1) ligand-binding site in the first domain.

P Stanley 1, A McDowall 1, P A Bates 1, J Brashaw 1, N Hogg 1
PMCID: PMC1221337  PMID: 10998349

Abstract

The first domain of intercellular adhesion molecule-1 (ICAM-1) binds to the leucocyte function-associated antigen-1 (LFA-1) I domain, which contains the principal ligand-binding site of this leucocyte integrin. Whether the function of the second domain is also to directly bind LFA-1 has been unclear. Our data show that mutation in the hydrophilic EF loop of ICAM-1 domain 2 resulted in impaired binding of the isolated I domain when compared with wild-type ICAM-1. LFA-1 on T-cells also binds with reduced affinity to this ICAM-1 mutant. A hybrid construct containing the first domain of vascular cell-adhesion molecule-1 joined to domains 2-5 of ICAM-1 was unable to bind to the I domain, showing that there is no direct interaction between the second domain of ICAM-1 and the I domain. This construct was also not bound by LFA-1 expressed in T-cells. Function-blocking monoclonal antibodies that map to domain 2 of ICAM-1, implicating this domain in ligand binding, were found to act indirectly. In summary our data suggest that the second domain of ICAM-1 has a role in maintaining the structure of the LFA-1 ligand-binding site in the first domain of ICAM-1 but does not appear to have a direct role in ligand binding.

Full Text

The Full Text of this article is available as a PDF (212.8 KB).

Selected References

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

  1. Bella J., Kolatkar P. R., Marlor C. W., Greve J. M., Rossmann M. G. The structure of the two amino-terminal domains of human ICAM-1 suggests how it functions as a rhinovirus receptor and as an LFA-1 integrin ligand. Proc Natl Acad Sci U S A. 1998 Apr 14;95(8):4140–4145. doi: 10.1073/pnas.95.8.4140. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Berendt A. R., McDowall A., Craig A. G., Bates P. A., Sternberg M. J., Marsh K., Newbold C. I., Hogg N. The binding site on ICAM-1 for Plasmodium falciparum-infected erythrocytes overlaps, but is distinct from, the LFA-1-binding site. Cell. 1992 Jan 10;68(1):71–81. doi: 10.1016/0092-8674(92)90207-s. [DOI] [PubMed] [Google Scholar]
  3. Berendt A. R., Simmons D. L., Tansey J., Newbold C. I., Marsh K. Intercellular adhesion molecule-1 is an endothelial cell adhesion receptor for Plasmodium falciparum. Nature. 1989 Sep 7;341(6237):57–59. doi: 10.1038/341057a0. [DOI] [PubMed] [Google Scholar]
  4. Binnerts M. E., van Kooyk Y., Simmons D. L., Figdor C. G. Distinct binding of T lymphocytes to ICAM-1, -2 or -3 upon activation of LFA-1. Eur J Immunol. 1994 Sep;24(9):2155–2160. doi: 10.1002/eji.1830240933. [DOI] [PubMed] [Google Scholar]
  5. Casasnovas J. M., Bickford J. K., Springer T. A. The domain structure of ICAM-1 and the kinetics of binding to rhinovirus. J Virol. 1998 Jul;72(7):6244–6246. doi: 10.1128/jvi.72.7.6244-6246.1998. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Casasnovas J. M., Pieroni C., Springer T. A. Lymphocyte function-associated antigen-1 binding residues in intercellular adhesion molecule-2 (ICAM-2) and the integrin binding surface in the ICAM subfamily. Proc Natl Acad Sci U S A. 1999 Mar 16;96(6):3017–3022. doi: 10.1073/pnas.96.6.3017. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Casasnovas J. M., Stehle T., Liu J. H., Wang J. H., Springer T. A. A dimeric crystal structure for the N-terminal two domains of intercellular adhesion molecule-1. Proc Natl Acad Sci U S A. 1998 Apr 14;95(8):4134–4139. doi: 10.1073/pnas.95.8.4134. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Diamond M. S., Staunton D. E., Marlin S. D., Springer T. A. Binding of the integrin Mac-1 (CD11b/CD18) to the third immunoglobulin-like domain of ICAM-1 (CD54) and its regulation by glycosylation. Cell. 1991 Jun 14;65(6):961–971. doi: 10.1016/0092-8674(91)90548-d. [DOI] [PubMed] [Google Scholar]
  9. Dransfield I., Cabañas C., Barrett J., Hogg N. Interaction of leukocyte integrins with ligand is necessary but not sufficient for function. J Cell Biol. 1992 Mar;116(6):1527–1535. doi: 10.1083/jcb.116.6.1527. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Duperray A., Languino L. R., Plescia J., McDowall A., Hogg N., Craig A. G., Berendt A. R., Altieri D. C. Molecular identification of a novel fibrinogen binding site on the first domain of ICAM-1 regulating leukocyte-endothelium bridging. J Biol Chem. 1997 Jan 3;272(1):435–441. doi: 10.1074/jbc.272.1.435. [DOI] [PubMed] [Google Scholar]
  11. Dustin M. L., Rothlein R., Bhan A. K., Dinarello C. A., Springer T. A. Induction by IL 1 and interferon-gamma: tissue distribution, biochemistry, and function of a natural adherence molecule (ICAM-1). J Immunol. 1986 Jul 1;137(1):245–254. [PubMed] [Google Scholar]
  12. Fisher K. L., Lu J., Riddle L., Kim K. J., Presta L. G., Bodary S. C. Identification of the binding site in intercellular adhesion molecule 1 for its receptor, leukocyte function-associated antigen 1. Mol Biol Cell. 1997 Mar;8(3):501–515. doi: 10.1091/mbc.8.3.501. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Gahmberg C. G., Tolvanen M., Kotovuori P. Leukocyte adhesion--structure and function of human leukocyte beta2-integrins and their cellular ligands. Eur J Biochem. 1997 Apr 15;245(2):215–232. doi: 10.1111/j.1432-1033.1997.00215.x. [DOI] [PubMed] [Google Scholar]
  14. Goodman T. G., Bajt M. L. Identifying the putative metal ion-dependent adhesion site in the beta2 (CD18) subunit required for alphaLbeta2 and alphaMbeta2 ligand interactions. J Biol Chem. 1996 Sep 27;271(39):23729–23736. doi: 10.1074/jbc.271.39.23729. [DOI] [PubMed] [Google Scholar]
  15. Greve J. M., Davis G., Meyer A. M., Forte C. P., Yost S. C., Marlor C. W., Kamarck M. E., McClelland A. The major human rhinovirus receptor is ICAM-1. Cell. 1989 Mar 10;56(5):839–847. doi: 10.1016/0092-8674(89)90688-0. [DOI] [PubMed] [Google Scholar]
  16. Holness C. L., Bates P. A., Little A. J., Buckley C. D., McDowall A., Bossy D., Hogg N., Simmons D. L. Analysis of the binding site on intercellular adhesion molecule 3 for the leukocyte integrin lymphocyte function-associated antigen 1. J Biol Chem. 1995 Jan 13;270(2):877–884. doi: 10.1074/jbc.270.2.877. [DOI] [PubMed] [Google Scholar]
  17. Jones E. Y., Harlos K., Bottomley M. J., Robinson R. C., Driscoll P. C., Edwards R. M., Clements J. M., Dudgeon T. J., Stuart D. I. Crystal structure of an integrin-binding fragment of vascular cell adhesion molecule-1 at 1.8 A resolution. Nature. 1995 Feb 9;373(6514):539–544. doi: 10.1038/373539a0. [DOI] [PubMed] [Google Scholar]
  18. Kirchhausen T., Staunton D. E., Springer T. A. Location of the domains of ICAM-1 by immunolabeling and single-molecule electron microscopy. J Leukoc Biol. 1993 Mar;53(3):342–346. doi: 10.1002/jlb.53.3.342. [DOI] [PubMed] [Google Scholar]
  19. Klickstein L. B., York M. R., Fougerolles A. R., Springer T. A. Localization of the binding site on intercellular adhesion molecule-3 (ICAM-3) for lymphocyte function-associated antigen 1 (LFA-1). J Biol Chem. 1996 Sep 27;271(39):23920–23927. doi: 10.1074/jbc.271.39.23920. [DOI] [PubMed] [Google Scholar]
  20. Kyte J., Doolittle R. F. A simple method for displaying the hydropathic character of a protein. J Mol Biol. 1982 May 5;157(1):105–132. doi: 10.1016/0022-2836(82)90515-0. [DOI] [PubMed] [Google Scholar]
  21. Landis R. C., Bennett R. I., Hogg N. A novel LFA-1 activation epitope maps to the I domain. J Cell Biol. 1993 Mar;120(6):1519–1527. doi: 10.1083/jcb.120.6.1519. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Languino L. R., Plescia J., Duperray A., Brian A. A., Plow E. F., Geltosky J. E., Altieri D. C. Fibrinogen mediates leukocyte adhesion to vascular endothelium through an ICAM-1-dependent pathway. Cell. 1993 Jul 2;73(7):1423–1434. doi: 10.1016/0092-8674(93)90367-y. [DOI] [PubMed] [Google Scholar]
  23. Larson R. S., Corbi A. L., Berman L., Springer T. Primary structure of the leukocyte function-associated molecule-1 alpha subunit: an integrin with an embedded domain defining a protein superfamily. J Cell Biol. 1989 Feb;108(2):703–712. doi: 10.1083/jcb.108.2.703. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Miller J., Knorr R., Ferrone M., Houdei R., Carron C. P., Dustin M. L. Intercellular adhesion molecule-1 dimerization and its consequences for adhesion mediated by lymphocyte function associated-1. J Exp Med. 1995 Nov 1;182(5):1231–1241. doi: 10.1084/jem.182.5.1231. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Newham P., Craig S. E., Seddon G. N., Schofield N. R., Rees A., Edwards R. M., Jones E. Y., Humphries M. J. Alpha4 integrin binding interfaces on VCAM-1 and MAdCAM-1. Integrin binding footprints identify accessory binding sites that play a role in integrin specificity. J Biol Chem. 1997 Aug 1;272(31):19429–19440. doi: 10.1074/jbc.272.31.19429. [DOI] [PubMed] [Google Scholar]
  26. Ockenhouse C. F., Betageri R., Springer T. A., Staunton D. E. Plasmodium falciparum-infected erythrocytes bind ICAM-1 at a site distinct from LFA-1, Mac-1, and human rhinovirus. Cell. 1992 Jan 10;68(1):63–69. doi: 10.1016/0092-8674(92)90206-r. [DOI] [PubMed] [Google Scholar]
  27. Osborn L., Vassallo C., Benjamin C. D. Activated endothelium binds lymphocytes through a novel binding site in the alternately spliced domain of vascular cell adhesion molecule-1. J Exp Med. 1992 Jul 1;176(1):99–107. doi: 10.1084/jem.176.1.99. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Randi A. M., Hogg N. I domain of beta 2 integrin lymphocyte function-associated antigen-1 contains a binding site for ligand intercellular adhesion molecule-1. J Biol Chem. 1994 Apr 29;269(17):12395–12398. [PubMed] [Google Scholar]
  29. Reilly P. L., Woska J. R., Jr, Jeanfavre D. D., McNally E., Rothlein R., Bormann B. J. The native structure of intercellular adhesion molecule-1 (ICAM-1) is a dimer. Correlation with binding to LFA-1. J Immunol. 1995 Jul 15;155(2):529–532. [PubMed] [Google Scholar]
  30. Rothlein R., Czajkowski M., Kishimoto T. K. Intercellular adhesion molecule-1 in the inflammatory response. Chem Immunol. 1991;50:135–142. [PubMed] [Google Scholar]
  31. Sadhu C., Lipsky B., Erickson H. P., Hayflick J., Dick K. O., Gallatin W. M., Staunton D. E. LFA-1 binding site in ICAM-3 contains a conserved motif and non-contiguous amino acids. Cell Adhes Commun. 1994 Oct;2(5):429–440. doi: 10.3109/15419069409004453. [DOI] [PubMed] [Google Scholar]
  32. Sanejouand Y. H. Normal-mode analysis suggests important flexibility between the two N-terminal domains of CD4 and supports the hypothesis of a conformational change in CD4 upon HIV binding. Protein Eng. 1996 Aug;9(8):671–677. doi: 10.1093/protein/9.8.671. [DOI] [PubMed] [Google Scholar]
  33. Simmons D., Makgoba M. W., Seed B. ICAM, an adhesion ligand of LFA-1, is homologous to the neural cell adhesion molecule NCAM. Nature. 1988 Feb 18;331(6157):624–627. doi: 10.1038/331624a0. [DOI] [PubMed] [Google Scholar]
  34. Springer T. A. Traffic signals for lymphocyte recirculation and leukocyte emigration: the multistep paradigm. Cell. 1994 Jan 28;76(2):301–314. doi: 10.1016/0092-8674(94)90337-9. [DOI] [PubMed] [Google Scholar]
  35. Stanley P., Bates P. A., Harvey J., Bennett R. I., Hogg N. Integrin LFA-1 alpha subunit contains an ICAM-1 binding site in domains V and VI. EMBO J. 1994 Apr 15;13(8):1790–1798. doi: 10.1002/j.1460-2075.1994.tb06447.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Stanley P., Hogg N. The I domain of integrin LFA-1 interacts with ICAM-1 domain 1 at residue Glu-34 but not Gln-73. J Biol Chem. 1998 Feb 6;273(6):3358–3362. doi: 10.1074/jbc.273.6.3358. [DOI] [PubMed] [Google Scholar]
  37. Staunton D. E., Dustin M. L., Erickson H. P., Springer T. A. The arrangement of the immunoglobulin-like domains of ICAM-1 and the binding sites for LFA-1 and rhinovirus. Cell. 1990 Apr 20;61(2):243–254. doi: 10.1016/0092-8674(90)90805-o. [DOI] [PubMed] [Google Scholar]
  38. Tian L., Kilgannon P., Yoshihara Y., Mori K., Gallatin W. M., Carpén O., Gahmberg C. G. Binding of T lymphocytes to hippocampal neurons through ICAM-5 (telencephalin) and characterization of its interaction with the leukocyte integrin CD11a/CD18. Eur J Immunol. 2000 Mar;30(3):810–818. doi: 10.1002/1521-4141(200003)30:3<810::AID-IMMU810>3.0.CO;2-X. [DOI] [PubMed] [Google Scholar]
  39. Wang J., Springer T. A. Structural specializations of immunoglobulin superfamily members for adhesion to integrins and viruses. Immunol Rev. 1998 Jun;163:197–215. doi: 10.1111/j.1600-065x.1998.tb01198.x. [DOI] [PubMed] [Google Scholar]
  40. Weber K. S., York M. R., Springer T. A., Klickstein L. B. Characterization of lymphocyte function-associated antigen 1 (LFA-1)-deficient T cell lines: the alphaL and beta2 subunits are interdependent for cell surface expression. J Immunol. 1997 Jan 1;158(1):273–279. [PubMed] [Google Scholar]
  41. de Fougerolles A. R., Qin X., Springer T. A. Characterization of the function of intercellular adhesion molecule (ICAM)-3 and comparison with ICAM-1 and ICAM-2 in immune responses. J Exp Med. 1994 Feb 1;179(2):619–629. doi: 10.1084/jem.179.2.619. [DOI] [PMC free article] [PubMed] [Google Scholar]

Articles from Biochemical Journal are provided here courtesy of The Biochemical Society

RESOURCES