C-CAM is a cell adhesion molecule belonging to the immunoglobulin supergene family and is known to mediate calcium-independent homophilic cell-cell binding. Two major isoforms, C-CAM1 and C-CAM2, which differ in their cytoplasmic domains, have been identified. Previous investigations have demonstrated that both cytoplasmic domains can bind calmodulin in a calcium-dependent reaction. In this investigation, peptides corresponding to the cytoplasmic domains of C-CAM were synthesized on cellulose membranes and used to map the binding sites for I-labeled calmodulin. Both C-CAM1 and C-CAM2 had one strong calmodulin-binding site in the membrane-proximal region. These binding regions were conserved in C-CAM from rat, mouse, and man. In addition, C-CAM1 from rat and mouse contained a weaker binding site in the distal region of the cytoplasmic domain. Biosensor experiments were performed to determine rate and equilibrium constants of the C-CAM/calmodulin interaction. An association rate constant of 3.3 10M s and two dissociation rate constants of 2.2 10 and 3.1 10 s were determined. These correspond to equilibrium dissociation constants of 6.7 10 and 9.4 10M, respectively. In dot-blot binding experiments, it was found that binding of calmodulin causes a down-regulation of the homophilic self-association of C-CAM. This suggests that calmodulin can regulate the functional activity of C-CAM.

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