4c2a

Crystal Structure of High-Affinity von Willebrand Factor A1 domain with R1306Q and I1309V Mutations in Complex with High Affinity GPIb alpha

spinqualitylabelsall models 4c2a, resolution 2.08Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 4c2a is a 2 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 2.081Å Ligands: ACT, CA, CAC, PEG Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Disease VWF_HUMAN Defects in VWF are the cause of von Willebrand disease type 1 (VWD1) [MIM:193400. A common hemorrhagic disorder due to defects in von Willebrand factor protein and resulting in impaired platelet aggregation. Von Willebrand disease type 1 is characterized by partial quantitative deficiency of circulating von Willebrand factor, that is otherwise structurally and functionally normal. Clinical manifestations are mucocutaneous bleeding, such as epistaxis and menorrhagia, and prolonged bleeding after surgery or trauma. Defects in VWF are the cause of von Willebrand disease type 2 (VWD2) [MIM:613554. A hemorrhagic disorder due to defects in von Willebrand factor protein and resulting in impaired platelet aggregation. Von Willebrand disease type 2 is characterized by qualitative deficiency and functional anomalies of von Willebrand factor. It is divided in different subtypes including 2A, 2B, 2M and 2N (Normandy variant). The mutant VWF protein in types 2A, 2B and 2M are defective in their platelet-dependent function, whereas the mutant protein in type 2N is defective in its ability to bind factor VIII. Clinical manifestations are mucocutaneous bleeding, such as epistaxis and menorrhagia, and prolonged bleeding after surgery or trauma. Defects in VWF are the cause of von Willebrand disease type 3 (VWD3) [MIM:277480. A severe hemorrhagic disorder due to a total or near total absence of von Willebrand factor in the plasma and cellular compartments, also leading to a profound deficiency of plasmatic factor VIII. Bleeding usually starts in infancy and can include epistaxis, recurrent mucocutaneous bleeding, excessive bleeding after minor trauma, and hemarthroses. Function VWF_HUMAN Important in the maintenance of hemostasis, it promotes adhesion of platelets to the sites of vascular injury by forming a molecular bridge between sub-endothelial collagen matrix and platelet-surface receptor complex GPIb-IX-V. Also acts as a chaperone for coagulation factor VIII, delivering it to the site of injury, stabilizing its heterodimeric structure and protecting it from premature clearance from plasma. Publication Abstract from PubMed Activation by elongational flow of von Willebrand factor (VWF) is critical for primary hemostasis. Mutations causing type 2B von Willebrand Disease (VWD), platelet-type VWD (PT-VWD), and tensile force each increase affinity of the VWF A1 domain and platelet glycoprotein Ibalpha (GPIbalpha) for one another; however, the structural basis for these observations remains elusive. Directed evolution was used to discover a further gain-of-function mutation in A1 that shifts the long-range disulfide bond by one residue. We solved multiple crystal structures of this mutant A1 and A1 containing two VWD mutations complexed with GPIbalpha containing two PT-VWD mutations. We observed a gained interaction between A1 and the central leucine-rich repeats (LRR) of GPIbalpha, previously shown to be important at high shear stress, and verified its importance mutationally. These findings suggest that structural changes including central GPIbalpha LRR-A1 contact contribute to VWF affinity regulation. Among the mutant complexes, variation in contacts and poor complementarity between the GPIbalpha beta-finger and the region of A1 harboring VWD mutations leads us to hypothesize that the structures are on a pathway to, but have not yet reached, a force-induced super high affinity state. Towards the Structural Basis of Regulation of von Willebrand Factor Binding to Glycoprotein Ib.,Blenner MA, Dong X, Springer TA J Biol Chem. 2014 Jan 3. PMID:24391089 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Platelet glycoprotein

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