Thrombin interaction with platelet membrane glycoprotein Ib.
Platelet activation by low doses of thrombin allows the amplification thrombin formation and thereby plays an important role in the development of thrombi. Although thrombin-induced platelet activation is elicited via the cleavage of its specific receptor (TR), platelet membrane glycoprotein Ib (GPIb) is required for responses to low concentrations of thrombin, as evidenced from the observation that GPIb-deficient platelets are characterized by a decreased sensitivity to thrombin and a low rate of activation. Glycoprotein Ib is an integral membrane protein composed of two disulfide-linked chains noncovalently associated to glycoproteins IX and V. As the receptor of the von Willebrand factor (vWF), GPIb plays a main role in platelet adhesion to the subendothelium. There are 25,000 copies of GPIb at the platelet surface but only 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 GPIb-thrombin interaction by the C-terminal tail of hirudin, fibrin(ogen), and thrombomodulin indicates that thrombin exosite 1 is essential for GPIb binding. A hydrophylic domain located on the 45-kd N-terminal domain of GPIb alpha is involved in thrombin binding, and in particular, a stretch of negatively charged residues appears to make ionic interactions with thrombin. The same region of GPIb also contributes to the vWF binding site that should be very close to and even overlapping the thrombin-binding site. Despite GPIb and TR both interacting with thrombin exosite 1, the soluble fragment of GPIb does not modify the hydrolysis by thrombin of its target peptidic bond on TR, indicating that these two proteins bind to discrete subsites within exosite 1 and that the promoting effect of GPIb on TR-coupled responses depends on the anchorage of these proteins to the platelet membrane.
Jandrot-Perrus
M
M
Laboratoire de Recherche sur l'Hémostase et la Thrombose, Faculté de Médecine Xavier Bichat, Paris, France.
Bouton
M C
MC
Lanza
F
F
Guillin
M C
MC
D000595:Amino Acid Sequence; D000818:Animals; D002384:Catalysis; D006801:Humans; D008969:Molecular Sequence Data; D015539:Platelet Activation; D019038:Platelet Glycoprotein GPIb-IX Complex / Q000378:metabolism*; D018179:Receptors, Thrombin / Q000378:metabolism; D013917:Thrombin / Q000378:metabolism*; D014841:von Willebrand Factor / Q000378:metabolism
D019038:Platelet Glycoprotein GPIb-IX Complex; D018179:Receptors, Thrombin; D014841:von Willebrand Factor; D013917:Thrombin