Conserved regions in the cytoplasmic domains of the leukocyte integrin alpha L beta 2 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 alpha and beta subunits. To investigate this problem in the leukocyte integrin alpha L beta 2 (LFA-1), we generated a series of cytoplasmic truncation or internal substitution mutants of the alpha L and beta 2 cytoplasmic domains, and assessed their biochemical and functional properties upon ectopic expression in constitutively adherent cells. Expression of the alpha L beta 2 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 beta 2 cytoplasmic domain, which display functional interdependence. In addition, a conserved region (Arg733-Lys742) in the beta 2 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 alpha L beta 2 heterodimer. Analysis of deletion mutants of the alpha L subunit demonstrates a role of the conserved, membrane-proximal GFFKR motif in conferring stability to the alpha beta 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 alpha and beta subunits affects the dimerization and regulated function of the adhesion receptor.