title: Crystal structure and binding properties of the CD2 and CD244 (2B4)-binding protein, CD48.
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.
authors.affiliation: 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.
authors.forename: Edward J
authors.initials: EJ
authors.lastname: Evans
authors.forename: Mónica A A
authors.initials: MA
authors.lastname: Castro
authors.forename: Ronan
authors.initials: R
authors.lastname: O'Brien
authors.forename: Alice
authors.initials: A
authors.lastname: Kearney
authors.forename: Heather
authors.initials: H
authors.lastname: Walsh
authors.forename: Lisa M
authors.initials: LM
authors.lastname: Sparks
authors.forename: Michael G
authors.initials: MG
authors.lastname: Tucknott
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Davies
authors.forename: Alexandre M
authors.initials: AM
authors.lastname: Carmo
authors.forename: P Anton
authors.initials: PA
authors.lastname: van der Merwe
authors.forename: David I
authors.initials: DI
authors.lastname: Stuart
authors.forename: E Yvonne
authors.initials: EY
authors.lastname: Jones
authors.forename: John E
authors.initials: JE
authors.lastname: Ladbury
authors.forename: Shinji
authors.initials: S
authors.lastname: Ikemizu
authors.forename: Simon J
authors.initials: SJ
authors.lastname: Davis
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000737:chemistry* / Q000378:metabolism; D018801:CD2 Antigens / Q000737:chemistry* / Q000378:metabolism; D000071178:CD48 Antigen; D018968:CD58 Antigens / Q000737:chemistry; D019143:Evolution, Molecular; D006801:Humans; D008024:Ligands; D008562:Membrane Glycoproteins / Q000737:chemistry* / Q000378:metabolism; D008958:Models, Molecular; D011485:Protein Binding; D011487:Protein Conformation; D017434:Protein Structure, Tertiary; D051381:Rats; D011971:Receptors, Immunologic / Q000737:chemistry* / Q000378:metabolism; D000071176:Signaling Lymphocytic Activation Molecule Family; D013816:Thermodynamics
chemical_list: D015703:Antigens, CD; D018801:CD2 Antigens; D000071178:CD48 Antigen; C000604065:CD48 protein, human; D018968:CD58 Antigens; C490008:Cd244 protein, rat; C000604066:Cd48 protein, mouse; C000604067:Cd48 protein, rat; D008024:Ligands; D008562:Membrane Glycoproteins; D011971:Receptors, Immunologic; D000071176:Signaling Lymphocytic Activation Molecule Family