TOPOLOGY OF THE CD2-CD48 CELL-ADHESION MOLECULE COMPLEX - IMPLICATIONS FOR ANTIGEN RECOGNITION BY T-CELLS

Background: The T-lymphocyte cell-surface molecule, CD2, was the first heterophilic cell-adhesion molecule to be discovered and has become a n important paradigm for understanding the structural basis of cell ad hesion. Interaction of CD2 with its ligands, CD58 (in humans) and CD48 (in mice and rats), contributes to antigen recognition by T cells. CD 2, CD48 and CD58 are closely related members of the immunoglobulin sup erfamily and their extracellular regions are predicted to have very si milar structures. The three-dimensional crystal structure of this regi on of CD2 has been determined, revealing two immunoglobulin domains wi th the ligand-binding site situated on an exposed beta sheet in the me mbrane-distal domain. This GFCC'C'' beta sheet is also involved in a h omophilic 'head-to-head' interaction in the CD2 crystal lattice, which has been proposed to be a model for the interactions of CD2 with ia l igands. Results: We show that the CD2-binding site on rat CD48 lies on the equivalent beta-sheet of its membrane-distal immunoglobulin domai n. By making complementary mutations, we have shown that two charged r esidues in the CD48 ligand-binding site interact directly with two opp ositely charged residues in CD2's ligand-binding site. These results i ndicate that the amino-terminal immunoglobulin domains of CD2 and CD48 bind each other in the same orientation as the CD2-CD2 crystal lattic e interaction, strongly supporting the suggestion that CD2 interacts h ead-to-head with its ligand. Modelling CD48 onto the CD? structure rev eals that the CD2-CD48 complex spans approximately the same distance ( 134 Angstrom) as predicted for the complex between the T-cell receptor and the peptide-bound major histocompatibility complex (MHC) molecule . Conclusions: Our results, together with recent structural studies of CD2, provide the first indication of the specific topology of a cell- adhesion molecule complex. The similar dimensions predicted for the CD 2-CD48 complex and the complex between the T-cell receptor and the pep tide-bound MHC molecule suggest that one of the functions of CD2 may b e to position the plasma membranes of the T cell and the antigen-prese nting (or target) cell at the optimal distance for the low-affinity in teraction between the T-cell receptor and the peptide-bound MHC molecu le.