{Reference Type}: Journal Article
{Title}: Ligand binding initiates single-molecule integrin conformational activation.
{Author}: Li J;Jo MH;Yan J;Hall T;Lee J;López-Sánchez U;Yan S;Ha T;Springer TA;
{Journal}: Cell
{Volume}: 187
{Issue}: 12
{Year}: 2024 Jun 6
{Factor}: 66.85
{DOI}: 10.1016/j.cell.2024.04.049
{Abstract}: Integrins link the extracellular environment to the actin cytoskeleton in cell migration and adhesiveness. Rapid coordination between events outside and inside the cell is essential. Single-molecule fluorescence dynamics show that ligand binding to the bent-closed integrin conformation, which predominates on cell surfaces, is followed within milliseconds by two concerted changes, leg extension and headpiece opening, to give the high-affinity integrin conformation. The extended-closed integrin conformation is not an intermediate but can be directly accessed from the extended-open conformation and provides a pathway for ligand dissociation. In contrast to ligand, talin, which links the integrin β-subunit cytoplasmic domain to the actin cytoskeleton, modestly stabilizes but does not induce extension or opening. Integrin activation is thus initiated by outside-in signaling and followed by inside-out signaling. Our results further imply that talin binding is insufficient for inside-out integrin activation and that tensile force transmission through the ligand-integrin-talin-actin cytoskeleton complex is required.