THROMBIN INTERACTION WITH PLATELET MEMBRANE GLYCOPROTEIN IB

Platelet activation by low doses of thrombin allows the amplification of thrombin formation and thereby plays an important role in the devel opment of thrombi. Although thrombin-induced platelet activation is el icited via the cleavage of its specific receptor (TR), platelet membra ne glycoprotein Ib (GPIb) is required for responses to low concentrati ons of thrombin, as evidenced from the observation that GPIb-deficient platelets are characterized by a decreased sensitivity to thrombin an d a low rate of activation. Glycoprotein Ib is an integral membrane pr otein composed of two disulfide-linked chains noncovalently associated to glycoproteins IX and V. As the receptor of the von Willebrand fact or (vWF), GPIb plays a main role in platelet adhesion to the subendoth elium. There are 25,000 copies of GPIb at the platelet surface but onl y a limited number of them appear to be involved in the high-affinity binding of thrombin. The catalytic site of thrombin is not involved in the interaction with GPIb. In contrast, competitive inhibition of GPI b-thrombin interaction by the C-terminal tail of hirudin, fibrin(ogen) , and thrombomodulin indicates that thrombin exosite 1 is essential fo r GPIb binding. A hydrophylic domain located on the 45-kd N-terminal d omain of GPIb alpha is involved in thrombin binding, and in particular , a stretch of negatively charged residues appears to make ionic inter actions with thrombin. The same region of GPIb also contributes to the vWF binding site that should be very close to and even overlapping th e thrombin-binding site. Despite GPIb and TR both interacting with thr ombin exosite 1, the soluble fragment of GPIb does not modify the hydr olysis by thrombin of its target pepbind to discrete subsites within e xosite 1 and that the promoting effect of GPIb on TR-coupled responses depends on the anchorage of these proteins to the platelet membrane.