title: 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 αIIbβ3 and occurs when platelet agonists generated at the injury site convert αIIbβ3 from its resting to its active conformation. Active αIIbβ3 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 αIIbβ3 ligand fibrinogen. Thus, αIIbβ3 activity is tightly regulated to prevent the spontaneous formation of platelet aggregates. αIIbβ3 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 αIIb and β3 maintain αIIbβ3 in its inactive conformation. Transmembrane domain interactions appear particularly important because disrupting these interactions causes constitutive αIIbβ3 activation. Second, the agonist-stimulated binding of the cytosolic proteins talin and kindlin-3 to the β3 cytosolic tail rapidly causes αIIbβ3 activation by disrupting the intramolecular interactions constraining αIIbβ3 activity. Third, the strength of ligand binding to active αIIbβ3 seems to be allosterically regulated. Thus, αIIbβ3 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.
authors.affiliation: Hematology-Oncology Division, Department of Medicine, Perelman School of Medicine, University of Pennsylvania Philadelphia, 19104, Pennsylvania.
authors.forename: Joel S
authors.initials: JS
authors.lastname: Bennett
mesh_terms: D020816:Amino Acid Motifs; D000818:Animals; D001792:Blood Platelets / Q000378:metabolism*; D002462:Cell Membrane / Q000378:metabolism*; D006801:Humans; D010974:Platelet Aggregation / Q000502:physiology*; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000378:metabolism*; D017434:Protein Structure, Tertiary
chemical_list: D019039:Platelet Glycoprotein GPIIb-IIIa Complex
keywords: cytosolic domains; integrins; optical tweezers; transmembrane domains; αIIbβ3