Molecular basis for the hemophilic activated leukocyte cell adhesion molecule (ALCAM)-ALCAM interaction

Activated leukocyte cell adhesion molecule (ALCAM/ CD166), a member of the immunoglobulin superfamily with five extracellular immunoglobulin-like doma ins, facilitates heterophilic (ALCAM-CD6) and hemophilic (ALCAM-ALCAM) cell -cell interactions, While expressed in a wide variety of tissues and cells, ALCAM is restricted to subsets of cells usually involved in dynamic growth and/or migration processes. A structure-function analysis, using two monoc lonal anti-ALCAM antibodies and a series of amino-terminally deleted ALCAM constructs, revealed that hemophilic cell adhesion depended on ligand bindi ng mediated by the membrane-distal amino-terminal immunoglobulin domain and on avidity controlled by ALCAM clustering at the cell surface involving me mbrane-proximal immunoglobulin domains. Go-expression of a transmembrane AL CAM. deletion mutant, which lacks the ligand binding domain, and endogenous wild-type ALCAM inhibited hemophilic cell-cell interactions by interferenc e with ALCAM avidity, while hemophilic, soluble ligand binding remained una ltered. The extracellular structures of ALCAM thus provide two structurally and functionally distinguishable modules, one involved in ligand binding a nd the other in avidity. Functionality of both modules is required for stab le hemophilic ALCAM-ALCAM cell-cell adhesion.