Bistable regulation of integrin adhesiveness by a bipolar metal ion cluster

Integrin alpha(4)beta(7) mediates rolling adhesion in Ca2+ and Ca2+ + Mg2+, and firm adhesion in Mg2+ and Mn2+, mimicking the two key steps in leukocyte accumulation in inflamed vasculature. We mutated an interlinked linear array of three divalent cation-binding sites present in integrin beta-subunit I-like domains. The middle, metal ion dependent adhesion site ( MIDAS) is required for both rolling and firm adhesion. One polar site, that adjacent to MIDAS (ADMIDAS), is required for rolling because its mutation results in firm adhesion. The other polar site, the ligand-induced metal binding site ( LIMBS), is required for firm adhesion because its mutation results in rolling. The LIMBS mediates the positive regulatory effects of low Ca2+ concentrations, whereas the ADMIDAS mediates the negative regulatory effects of higher Ca2+ concentrations, which are competed by Mn2+. The bipolar sites thus stabilize two alternative phases of adhesion.