Conformational changes in the integrin βA domain provide a mechanism for signal transduction via hybrid domain movement

The ligand-binding head region of integrin β subunits contains a von Willebrand factor type A domain (βA). Ligand binding activity is regulated through conformational changes in βA, and ligand recognition also causes conformational changes that are transduced from this domain. The molecular basis of signal transduction to and from βA is uncertain. The epitopes of mAbs 15/7 and HUTS-4 lie in the β1 subunit hybrid domain, which is connected to the lower face of βA. Changes in the expression of these epitopes are induced by conformational changes in βA caused by divalent cations, function perturbing mAbs, or ligand recognition. Recombinant truncated α5β1 with a mutation L358A in the α7 helix of βA has constitutively high expression of the 15/7 and HUTS-4 epitopes, mimics the conformation of the ligand-occupied receptor, and has high constitutive ligand binding activity. The epitopes of 15/7 and HUTS-4 map to a region of the hybrid domain that lies close to an interface with the α subunit. Taken together, these data suggest that the transduction of conformational changes through βA involves shape shifting in the α7 helix region, which is linked to a swing of the hybrid domain away from the α subunit.