Differential regulation of α4 integrin-dependent binding to domains 1 and 4 of vascular cell adhesion molecule-1

Abstract

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 α4β1 integrin. Using a panel of VCAM-1 domain deletion mutants we show that α4β7 integrin interacts with both domains 1 and 4. In contrast to their identical domain usage, α4β1 and α4β7 integrins differ in the activation states required for binding to domains 1 and 4 of VCAM-1. We show that integrin α4β1 required significantly higher concentrations of Mn2+ than integrin α4β7 to support half-maximal adhesion to domain 4. Moreover, a clear difference in the capacity of integrins α4β1 and α4β7 to interact with domain 4 was detected in the presence of Ca2+ and Mg2+ cations. Adhesion to domain 1 of VCAM-1, however, was not affected by integrin heterodimer composition. Instead, the activity level of integrin α4β1 for domain 1 binding was regulated by CD24 expression. Binding to seven domain VCAM-1 was not altered significantly by β1 and β7 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.