The leukocyte integrin αxβ2 (p150,95) recognizes the iC3b complement fragment and functions as the complement receptor type 4. αxβ2 is more resistant to activation than other β2 integrins and is inactive in transfected cells. However, when human αx is paired with chicken or mouse β2, αxβ2 is activated for binding to iC3b. Activating substitutions were mapped to individual residues or groups of residues in the N-terminal plexin/semaphorin/integrin (PSI) domain and C-terminal cysteine-rich repeats 2 and 3. These regions are linked by a long range disulfide bond. Substitutions in the PSI domain synergized with substitutions in the cysteine-rich repeats. Substitutions T4P, T22A, Q525S, and V526L gave full activation. Activation of binding to iC3b correlated with exposure of the CBR LFA-1/2 epitope in cysteine-rich repeat 3. The data suggest that the activating substitutions are present in an interface that restrains the human αx/human β2 integrin in the inactive state. The opening of this interface is linked to structural rearrangements in other domains that activate ligand binding.
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