Review Regulation of Integrins in Platelets

Abstract

Blood platelets prevent bleeding after trauma by forming occlusive aggregates at sites of vascular injury. Platelet aggregation is mediated by the integrin heterodimer aIIbb3 and occurs when platelet agonists generated at the injury site convert aIIbb3 from its resting to its active conformation. Active aIIbb3 is then able to bind macromolecular ligands such as fibrinogen that crosslink adjacent platelets into hemostatic aggregates. Platelets circulate in a plasma milieu containing high concentrations of the principal aIIbb3 ligand fibrinogen. Thus, aIIbb3 activity is tightly regulated to prevent the spontaneous formation of platelet aggregates. aIIbb3 activity is regulated at least three levels. First, intramolecular interactions involving motifs located in the membraneproximal stalk regions, transmembrane domains, and the membrane-proximal cytosolic tails of aIIb and b3 maintain aIIbb3 in its inactive conformation. Transmembrane domain interactions appear particularly important because disrupting these interactions causes constitutive aIIbb3 activation. Second, the agonist-stimulated binding of the cytosolic proteins talin and kindlin-3 to the b3 cytosolic tail rapidly causes aIIbb3 activation by disrupting the intramolecular interactions constraining aIIbb3 activity. Third, the strength of ligand binding to active aIIbb3 seems to be allosterically regulated. Thus, aIIbb3 exists in a minimum of three interconvertible states: an inactive (resting) state that does not interact with ligands and two active ligand binding states that differ in their affinity for fibrinogen and in the mechanical stability of fibrinogen complexes they form.