Regulation of Integrins in Platelets

Blood platelets prevent bleeding after trauma by forming occlusive aggregates at sites of vascular injury. Platelet aggregation is mediated by the integrin heterodimer alpha IIb beta 3 and occurs when platelet agonists generated at the injury site convert alpha IIb beta 3 from its resting to its active conformation. Active alpha IIb beta 3 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 alpha IIb beta 3 ligand fibrinogen. Thus, alpha IIb beta 3 activity is tightly regulated to prevent the spontaneous formation of platelet aggregates. alpha IIb beta 3 activity is regulated at least three levels. First, intramolecular interactions involving motifs located in the membrane-proximal stalk regions, transmembrane domains, and the membrane-proximal cytosolic tails of alpha IIb and beta 3 maintain alpha IIb beta 3 in its inactive conformation. Transmembrane domain interactions appear particularly important because disrupting these interactions causes constitutive alpha IIb beta 3 activation. Second, the agonist-stimulated binding of the cytosolic proteins talin and kindlin-3 to the beta 3 cytosolic tail rapidly causes alpha IIb beta 3 activation by disrupting the intramolecular interactions constraining alpha IIb beta 3 activity. Third, the strength of ligand binding to active alpha IIb beta 3 seems to be allosterically regulated. Thus, alpha IIb beta 3 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. (C) 2015 Wiley Periodicals, Inc.