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