Differential activation of LFA-1 and Mac-1 ligand binding domains.

Nine integrin alpha subunits contain an 'inserted' or I-domain, known to involve in ligand binding. Mutation of an invariant isoleucine residue in the I-domains of alphaL and alphaM has previously been reported to activate LFA-1 and Mac-1, respectively. In this article, we report notable differences in the regulation of adhesion of these two integrins. We find that mutation of the isoleucine residue in the proposed "socket for isoleucine" in full-length alphaL does not lead to an active LFA-1, although mutation of the equivalent residue in alphaM does convey constitutive activity to Mac-1. In addition, we observe the isolated I-domain of alphaL to be constitutively active. This challenges reports that state the alphaL I-domain exists in an inactive, closed conformation, and requires the presence of activating agents for ligand binding. These results shed further light on the many questions surrounding regulation of integrin activation.