Activation of integrin β-subunit I-like domains by one-turn C-terminal α-helix deletions

摘要

Integrins contain two structurally homologous but distantly related domains: an I-like domain that is present in all β-subunits and an I domain that is present in some α-subunits. Atomic resolution and mutagenesis studies of α I domains demonstrate a C-terminal, axial displacement of the α7-helix that allosterically regulates the shape and affinity of the ligand-binding site. Atomic resolution studies of β I-like domains have thus far demonstrated no similar α7-helix displacement; however, other studies are consistent with the idea that α I and β I-like domains undergo structurally analogous rearrangements. To test the hypothesis that C-terminal, axial displacement of the α7-helix, coupled with β6–α7 loop reshaping, activates β I-like domains, we have mimicked the effect of α7-helix displacement on the β6–α7 loop by shortening the α7-helix by two independent, four-residue deletions of about one turn of α-helix. In the case of integrin αLβ2, each mutant exhibits constitutively high affinity for the physiological ligand intercellular adhesion molecule 1 and full exposure of a β I-like domain activation-dependent antibody epitope. In the case of analogous mutants in integrin α4β7, each mutant shows the activated phenotype of firm adhesion, rather than rolling adhesion, in shear flow. The results show that integrins that contain or lack α I domains share a common pathway of β I-like domain activation, and they suggest that β I-like and α I domain activation involves structurally analogous α7-helix axial displacements.