| Von Willebrand factor (vWF) is a multimeric plasma | | | | GPIbα is the largest subunit within the complex and |
| glycoprotein that mediates platelet adhesion to the | | | | is the only subunit implicated in ligand binding. The |
| subendothelium at sites of vascular injury. | | | | ligand-binding region resides within approximately 300 |
| Platelets are cytoplasmic fragments of mega | | | | amino acids at the GPIbα N terminus . The |
| karyocytes and, therefore, their membrane proteins | | | | ligand-binding region can be divided into three distinct |
| cannot be manipulated by expression methods in | | | | structural sub domains that are mixed in vWF binding |
| culture. Platelets participate in the physiologic | | | | including seven tandem leucine-rich repeats, disulfide |
| mechanisms that interrupt bleeding a process called | | | | loops flanking the leucine-rich repeats, and a highly |
| hemostasis by adhering to injured vascular surfaces | | | | negatively charged sequence spanning residues |
| and aggregating with one another. The pathological | | | | Asp-269 to Asp-287 . Three tyrosine residues |
| counterpart of this normal activity is the occurrence | | | | (Tyr-276, Tyr-278, and Tyr-279) are embedded in |
| of arterial thrombosis, caused by the formation of | | | | this negatively charged sequence and each is fully |
| thrombi that occlude atherosclerotic vessels and | | | | sulfated . |
| curtail blood supply to organs. Central to the function | | | | |
| of platelets is the interaction of adhesive molecules in | | | | It does so by forming a link between specific platelet |
| the vessel wall and blood with receptor glycoproteins | | | | membrane receptors and constituents of the |
| on the outer plasma membrane . | | | | subendothelial connective tissue. In addition, vWF |
| GPIb serves as one of the essential receptors for | | | | binds to and stabilizes blood coagulation factor VIII in |
| von Willebrand factor (vWF) and plays a crucial role in | | | | the circulation. vWF is synthesized from an 8.7-kb |
| platelet thrombus formation. Undeniably, the binding | | | | mRNA and appears to be expressed exclusively in |
| of multimeric vWF to GPIb results in platelet | | | | endothelial cells ECs and megakaryocytes. vWF is |
| activation and may lead to adhesion and aggregation . | | | | commonly used as an immunohistochemical marker |
| GPIbα is also a classical oncoprotein in which its | | | | for ECs. vWF is a long protein which contained many |
| deregulated expression leads to transformation, | | | | domains and each domain meant for a significant |
| reduced growth factor requirements, increased | | | | functions. Here we have analyzed the structure and |
| resistance to apoptosis. GPIbα also promotes | | | | functions of A1, A2 and A3 domains of vWf in |
| double-stranded DNA breaks, and induces profound | | | | details. Furthermore, we found that vWF is directly |
| nuclear dysmorphology, indicating that, in addition to | | | | associated a large number of disease, that are |
| its direct transforming function, it also displays | | | | known as von Willebrand disease. The expression of |
| genotoxicity at several distinct levels. | | | | the murine vWF gene usually downregulated by LPS |
| GPIbα contributes to arterial thrombosis by adhesion | | | | in many tissues. Domain A identifies a superfamily of |
| mechanisms independent of the binding to vWF. | | | | proteins involved in biological processes controlled by |
| Platelet adhesion to the extracellular matrix (ECM) is a | | | | specific molecular interactions, often adhesive in |
| key step in thrombus formation as found in | | | | nature which interacts with cell surface receptor |
| hemostasis and thrombosis. The interaction of | | | | integrin. vWF is known to perform a large number of |
| platelet receptor GPIbα and vWF exposed in the | | | | functions in human body including cell surface |
| extracellular matrix is commonly accepted as the key | | | | receptor binding, blood coagulation and maintaining |
| event required for the initial tethering of platelets | | | | body stress. |
| along the damaged vascular wall, especially under | | | | When the endothelium is disrupted, vWF binds to |
| conditions of high shear stress . The GPIb-V-IX | | | | collagen of the sub endothelium. In areas of low |
| receptor complex consists of four gene products, | | | | blood flow rate, platelets may adhere to vessel walls |
| GPIbα, GPIbβ, GPIX, and GPV (Lopez JA, 1994). | | | | independently of vWF. In areas with a high blood |
| Approximately 25,000 copies of GPIb-IX and 12,000 | | | | flow rate, vWF is necessary for the platelets to |
| copies of GPV are expressed on resting platelets. | | | | adhere to the sub endothelium. Although some vWF |
| The ligand-binding site for vWF is located within the | | | | is located in the sub endothelium, additional vWF is |
| 45-kDa N-terminal region of GPIbα. | | | | needed for an optimal platelet adhesion. In such |
| GPIb-V-IX complex plays an important role in vascular | | | | instances, additional vWF is released from platelet or |
| biology. It is involved in the interaction between | | | | endothelial cell granules. As vWF binds to exposed |
| resting platelets and activated leukocytes by its | | | | collagen, its conformation changes allowing an |
| binding to Mac-1 and activated endothelial cells by its | | | | increased binding affinity for glycoprotein Ib located |
| binding to P-selectin. GPIbα also interacts with | | | | on the platelet membrane. Platelets subsequently bind |
| thrombin , high molecular weight kininogen, coagulation | | | | to vWF and adhere to the vessel wall. Once the |
| factors XI and XII, and TSP-1 . On binding of a ligand | | | | platelets are activated, they expose their |
| the GPIb-V-IX receptor complex induces signals | | | | fibrinogen-binding sites (glycoprotein IIb-IIIa). |
| leading to calcium mobilization, rearrangement of the | | | | Fibrinogen adheres and further aggregation of |
| cytoskeleton, granule release, and activation of | | | | platelets occurs. vWF may also bind to platelets to |
| αIIbβ3 integrin . | | | | stabilize their attachment. |
| The importance of the GPIb-V-IX receptor for | | | | The crystal structure of all three domains is |
| hemostasis is shown by the strong bleeding diathesis | | | | determined and interestingly, all three domains share |
| found in Bernard–Soulier syndrome (BSS) patients | | | | identical three dimensional fold with a-b-a sandwiched |
| lacking the GPIb-V-IX complex on the platelet surface | | | | model. Here we have extensively studied the clinical |
| or in patients lacking VWF. | | | | significance of vWF with respect to its functions and |
| Glycoprotein Ibα (GP Ibα), the ligand binding subunit | | | | structure. We hope that this review may be a |
| of the platelet glycoprotein Ib-IX-V complex, is | | | | valuable to for researcher who are working in the |
| sulfated on three tyrosine residues (Tyr-276, | | | | similar field. |
| Tyr-278, and Tyr-279). | | | | |