Type of Document Master's Thesis Author Drahos, Karen Elizabeth Author's Email Address firstname.lastname@example.org URN etd-04042009-232708 Title Sulfatides mediate Disabled-2 membrane localization and stability during platelet aggregation. Degree Master of Science Department Biology Advisory Committee
Advisor Name Title Finkielstein, Carla V. Committee Chair Capelluto, Daniel G. S. Committee Member Sible, Jill C. Committee Member Keywords
Date of Defense 2009-03-23 Availability unrestricted AbstractThrombosis, the major cause of heart attack and strokes,1 is triggered by localized clotting of the blood as the result of deregulated platelet aggregation. During the repair of vascular injury, clotting usually occurs when platelets adhere to each other at the site of vascular injury in order to stop bleeding.2 Distinct protein receptors and adhesive ligands together with the blood flow conditions govern this process. One of the negative regulators in platelet aggregation is Disabled-2 (Dab2), a modular protein that is released upon platelet activation to the extracellular platelet surface.3 Dab2 inhibits platelet aggregation through its phosphotyrosine-binding (PTB) domain by competing with fibrinogen for II3 integrin binding on the activated platelet surface.3 Sulfatides are also found on the platelet surface,4 interacting with adhesive and coagulation proteins5-7 and, thus, they are thought to play a major role in haemostasis and thrombogenesis.
Here, we show that the Dab2 PTB domain specifically interacts with sulfatides through two conserved basic motifs. The sulfatide-binding site overlaps with that of phosphatidylinositol 4,5-biphosphate (PtdIns(4,5)P2) in the PTB domain. Whereas sulfatides recruit the Dab2 PTB domain to the platelet surface, thus sequestering the protein from thrombin-mediated platelet aggregation, the phosphoinositide mediates its internalization. Experimental data support the hypothesis that two pools of Dab2 co-exist at the platelet surface and that the balance between them controls the extent of the clotting response.
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