Crystal Structure and Binding Properties of the CD2 and CD244 (2B4)-binding Protein, CD48*

  1. Edward J. Evans ‡ ,
  2. Mónica A. A. Castro § 1 ,
  3. Ronan O'Brien ,
  4. Alice Kearney ∥ ,
  5. Heather Walsh ‡ ,
  6. Lisa M. Sparks ‡ ,
  7. Michael G. Tucknott ∥ ,
  8. Elizabeth A. Davies ∥ ,
  9. Alexandre M. Carmo § 1 ,
  10. P. Anton van der Merwe ∥ 2 ,
  11. David I. Stuart ** 2 ,
  12. E. Yvonne Jones ** 3 ,
  13. John E. Ladbury ,
  14. Shinji Ikemizu ‡‡ 4 and
  15. Simon J. Davis ‡ 5
  1. ‡Nuffield Department of Clinical Medicine, The University of Oxford and MRC Human Immunology Unit, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, Headington, Oxford OX3 9DS, United Kingdom, the §Group of Cell Activation and Gene Expression, IBMC-Instituto de Biologia Molecular e Celular and ICBAS-Instituto de Ciências Biomédicas de Abel Salazar, Universidade do Porto, 4099-003 Porto, Portugal, the Department of Biochemistry and Molecular Biology, University College London, Gower Street, London WC1E 6BT, United Kingdom, the ∥Sir William Dunn School of Pathology, The University of Oxford, South Parks Road, Oxford OX1 3RE, United Kingdom, the **Division of Structural Biology, Wellcome Trust Centre for Human Genetics, The University of Oxford, Roosevelt Drive, Oxford OX3 7BN, United Kingdom, and the ‡‡Division of Structural Biology, Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-honmachi, Kumamoto 862-0973, Japan
  1. 4 Supported by Grants-in-Aid from the Ministry of Education, Culture, Sports, Science and Technology of Japan. To whom correspondence may be addressed: Tel./Fax.: 81-96-371-4647; E-mail: ikemizu{at}gpo.kumamoto-u.ac.jp.
  2. 5 Supported by Grants-in-Aid from the Ministry of Education, Culture, Sports, Science and Technology of Japan. To whom correspondence may be addressed: Tel./Fax.: 81-96-371-4647; E-mail: ikemizu{at}gpo.kumamoto-u.ac.jp.5 Supported by the Wellcome Trust. To whom correspondence may be addressed. Tel.: 44-1865-221-336; Fax: 44-1865-222-737; E-mail: simon.davis{at}ndm.ox.ac.uk.

Abstract

The structural analysis of surface proteins belonging to the CD2 subset of the immunoglobulin superfamily has yielded important insights into transient cellular interactions. In mice and rats, CD2 and CD244 (2B4), which are expressed predominantly on T cells and natural killer cells, respectively, bind the same, broadly expressed ligand, CD48. Structures of CD2 and CD244 have been solved previously, and we now present the structure of the receptor-binding domain of rat CD48. The receptor-binding surface of CD48 is unusually flat, as in the case of rat CD2, and shares a high degree of electrostatic complementarity with the equivalent surface of CD2. The relatively simple arrangement of charged residues and this flat topology explain why CD48 cross-reacts with CD2 and CD244 and, in rats, with the CD244-related protein, 2B4R. Comparisons of modeled complexes of CD2 and CD48 with the complex of human CD2 and CD58 are suggestive of there being substantial plasticity in the topology of ligand binding by CD2. Thermodynamic analysis of the native CD48-CD2 interaction indicates that binding is driven by equivalent, weak enthalpic and entropic effects, in contrast to the human CD2-CD58 interaction, for which there is a large entropic barrier. Overall, the structural and biophysical comparisons of the CD2 homologues suggest that the evolutionary diversification of interacting cell surface proteins is rapid and constrained only by the requirement that binding remains weak and specific.

Footnotes

  • ↵6 The abbreviations used are: IgSF, immunoglobulin superfamily; s, soluble; r, rat; h, human; m, mouse; c, chimeric; WT, wild-type; PDB, Protein Data Bank; r.m.s.d., root mean square deviation; NK, natural killer cells; TCR, T-cell receptor.

  • ↵7 A. Kearney, A. Avramovic, M. A. A. Castro, A. M. Carmo, S. J. Davis, and P. A. van der Merwe, unpublished data.

  • ↵8 R. Esnouf, personal communication.

  • ↵9 E. J. Evans and S. J. Davis, unpublished data.

  • ↵10 A. V. Collins, D. W. Brodie, R. O'Brien, P. A. van der Merwe, S. J. Davis, and J. E. Ladbury, unpublished data.

  • ↵* The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

  • ↵Graphic The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. S1-S3.

  • ↵1 Supported by the Programa Operacional Ciênciae Inovação 2010 (POCI), co-funded by the European Regional Development Fund (FEDER).

  • ↵2 Supported by the UK Medical Research Council.

  • ↵3 Supported by Cancer Research UK.

    • Received February 10, 2006.
    • Revision received May 1, 2006.
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  1. First Published on June 27, 2006 doi: 10.1074/jbc.M601314200 The Journal of Biological Chemistry 281, 29309-29320.
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