Conserved regions in the cytoplasmic domains of the leukocyte integrin αLβ2 are involved in endoplasmic reticulum retention, dimerization, and cytoskeletal association

Selected functions of integrins, including regulated cytoskeletal association and transmembrane signaling, depend on a poorly defined bidirectional communication between the extracellular and cytoplasmic domains of the a and β subunits. To investigate this problem in the leukocyte integrin α₁β₂ (LFA-1), we generated a series of cytoplasmic truncation or internal substitution mutants of the α₁ and β₂ cytoplasmic domains, and assessed their biochemical and functional properties upon ectopic expression in constitutively adherent cells. Expression of the α₁β₂ heterodimer in stably adherent cells is sufficient to promote its constitutive cytoskeletal association. Structural determinants for such association are located in selected regions of the β₂ cytoplasmic domain, which display functional interdependence. In addition, a conserved region (Arg⁷³³-Lys⁷⁴²) in the β₂ cytoplasmic domain seems to be critical not only for its cytoskeletal association, but also for endoplasmic reticulum retention, assembly, and transport to the plasma membrane of the mature α₁β₂ heterodimer. Analysis of deletion mutants of the α₁ subunit demonstrates a role of the conserved, membrane-proximal GFFKR motif in conferring stability to the αβ complex, possibly because of its direct involvement in heterodimer formation. We propose that a previously uncharacterized association of defined subregions of the cytoplasmic domains of integrin a and β subunits affects the dimerization and regulated function of the adhesion receptor.