RECOGNITION OF DIVERSE PROTEINS BY MEMBERS OF THE IMMUNOGLOBULIN SUPERFAMILY - DELINEATION OF THE RECEPTOR-BINDING SITE IN THE HUMAN CD6 LIGAND ALCAM

The CD6-ALCAM (activated leukocyte cell adhesion molecule) interaction , which mediates thymocyte-thymic epithelial cell adhesion, is a previ ously unobserved type of protein-protein interaction that involves mem bers of the scavenger receptor cysteine rich protein superfamily (SRCR SF) and the immunoglobulin superfamily (IgSF). Targeted mutagenesis of ALCAM reveals that residues which constitute the CD6 binding site clu ster on the predicted A'GFCC'C '' face of its N-terminal Ig domain. Th ese results, in conjunction with recent analyses of interactions invol ving other IgSF members, suggest that this region in IgSF cell surface proteins is most suitable to mediate interactions with different liga nds irrespective of their structure. The CD6 binding site in ALCAM is conserved across species, and nonconserved residues in ALCAM and its m urine homolog map to the beta-sheet face opposite to the CD6 binding s ite. This provides a molecular rationale for the inability to obtain m urine monoclonal antibodies against the receptor binding domain which block the CD6-ALCAM, interaction.