The vascular cell adhesion molecule-1 (VCAM-1) plays an important role in diverse physiological and pathological processes. The homologous first and fourth immunoglobulin-like domains of the seven domain form of VCAM-1 present binding motifs for integrin. Using a panel of VCAM-1 domain deletion mutants we show that integrin interacts with both domains 1 and 4. In contrast to their identical domain usage, and integrins differ in the activation states required for binding to domains 1 and 4 of VCAM-1. We show that integrin required significantly higher concentrations of Mn than integrin to support half-maximal adhesion to domain 4. Moreover, a clear difference in the capacity of integrins and to interact with domain 4 was detected in the presence of Ca and Mg cations. Adhesion to domain 1 of VCAM-1, however, was not affected by integrin heterodimer composition. Instead, the activity level of integrin for domain 1 binding was regulated by CD24 expression. Binding to seven domain VCAM-1 was not altered significantly by and subunits or CD24. These data indicate that integrin heterodimer composition and CD24 expression differentially modulate integrin binding to domains 1 and 4 of VCAM-1. Mechanisms that alter integrin binding specificity or monovalent versus divalent interactions may affect the strength of adhesion as well as signal transmission in adherent cells and may therefore be critical to controlling the cellular response to integrin occupancy.

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