Talins and kindlins: partners in integrin-mediated adhesion

Integrins are transmembrane receptors that support adhesion to the extracellular matrix and transmit chemical and mechanical signals into and out of cells. Cells regulate integrin-mediated adhesion by controlling integrin affinity for extracellular ligands (integrin activation), by clustering integrins into adhesion complexes (avidity modulation) and by regulating links between integrin cytoplasmic domains and the actin cytoskeleton.The large dimeric actin-binding protein talin is a key regulator of integrin activation, and is composed of an amino-terminal head and a carboxy-terminal flexible rod. The structures of all 18 domains in talin have now been determined, and a model of full-length talin has been generated.Biochemical and structural data reveal how direct interactions between the short cytoplasmic tails of β-integrin subunits and the talin head (a FERM domain) disrupt inhibitory interactions between the integrin α-subunit and β-subunit, inducing conformational changes in the integrin extracellular domains that result in their increased affinity for ligand.The talin rod consists of 13 either 4- or 5-helix bundles, terminating in a single helix that supports talin dimerization. It contains two actin-binding sites and multiple binding sites for the actin-binding protein vinculin, which stabilizes adhesion complexes. Recent data show that the dynamic between talin–RIAM and talin–vinculin interactions is important for integrin activation and force-induced maturation of adhesions.Regulation of talin–integrin interactions represents an important control point along integrin activation pathways. Various regulatory mechanisms have been identified, including talin autoinhibition, competition between talin and other integrin tail-binding or talin-binding proteins and post-translational modification of β-integrin subunits.Although much less well-understood than talins, kindlin family proteins are also known to be important integrin regulators. Kindlin loss, due to knockout, knockdown or disease-causing mutations, result in defective integrin activation.The molecular basis of kindlin function has yet to be determined, but kindlins are structurally related to the talin head, directly bind β-integrin tails and membranes, localize to focal adhesions and synergize with talin during integrin activation.