The linkage of heterodimeric (␣/␤) integrin receptors with their extracellular matrix ligands and intracellular actin cytoskeleton is a fundamental step for controlling cell adhesion and migration.Binding of the actin-linking protein, talin, to integrin ␤ cytoplasmic tails (CTs) induces high affinity ligand binding (integrin activation), whereas binding of another actinlinking protein, filamin, to the integrin ␤ CTs negatively regulates this process by blocking the talin-integrin interaction. Here we show structurally that migfilin, a novel cytoskeletal adaptor highly enriched in the integrin adhesion sites, strongly interacts with the same region in filamin where integrin ␤ CTs bind. We further demonstrate that the migfilin interaction dissociates filamin from integrin and promotes the talin/integrin binding and integrin activation. Migfilin thus acts as a molecular switch to disconnect filamin from integrin for regulating integrin activation and dynamics of extracellular matrix-actin linkage.

antiviral mechanism ͉ autoinhibition ͉ NMR ͉ peptide activator ͉ protein kinase