Modulation of α-Thrombin Function by Distinct Interactions with Platelet Glycoprotein Ibα

• Published in: Science (American Association for the Advancement of Science) 2003-07, Vol.301 (5630), p.218-221
• Main Authors: Celikel, Reha, McClintock, Richard A., Roberts, James R., Mendolicchio, G. Loredana, Ware, Jerry, Varughese, Kottayil I., Ruggeri, Zaverio M.
• Format: Article
• Language: English
• Subjects: Biological and medical sciences; Blood; Blood coagulation. Blood cells; Clotting; Data collection; Fundamental and applied biological sciences. Psychology; Molecular and cellular biology; Molecular interactions; Molecular structure; Molecules; Platelet; Platelets; Receptors; Strong nuclear force; Thrombosis
• ISSN: 0036-8075; 1095-9203
• DOI: 10.1126/science.1084183

Thrombin bound to platelets contributes to stop bleeding and, in pathological conditions, may cause vascular thrombosis. We have determined the structure of platelet glycoprotein Ibα (GpIbα) bound to thrombin at 2.3 angstrom resolution and defined two sites in GpIbα that bind to exosite II and exosite I of two distinct α-thrombin molecules, respectively. GpIbα occupancy may be sequential, as the site binding to α-thrombin exosite I appears to be cryptic in the unoccupied receptor but exposed when a first thrombin molecule is bound through exosite II. These interactions may modulate α-thrombin function by mediating GpIbα clustering and cleavage of protease-activated receptors, which promote platelet activation, while limiting fibrinogen clotting through blockade of exosite I.