4c2b

Crystal Structure of High-Affinity von Willebrand Factor A1 domain with Disulfide Mutation in Complex with High Affinity GPIb alpha

spinqualitylabelsall models 4c2b, resolution 2.80Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 4c2b is a 8 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: MES, PEG, SO4 Related: 4c29, 4c2a 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. [GP1BA_HUMAN] Genetic variations in GP1BA may be a cause of susceptibility to non-arteritic anterior ischemic optic neuropathy (NAION) [MIM:258660]. NAION is an ocular disease due to ischemic injury to the optic nerve. It usually affects the optic disk and leads to visual loss and optic disk swelling of a pallid nature. Visual loss is usually sudden, or over a few days at most and is usually permanent, with some recovery possibly occurring within the first weeks or months. Patients with small disks having smaller or non-existent cups have an anatomical predisposition for non-arteritic anterior ischemic optic neuropathy. As an ischemic episode evolves, the swelling compromises circulation, with a spiral of ischemia resulting in further neuronal damage. Defects in GP1BA are a cause of Bernard-Soulier syndrome (BSS) [MIM:231200]; also known as giant platelet disease (GPD). BSS patients have unusually large platelets and have a clinical bleeding tendency. Defects in GP1BA are the cause of benign mediterranean macrothrombocytopenia (BMM) [MIM:153670]; also known as autosomal dominant benign Bernard-Soulier syndrome. BMM is characterized by mild or no clinical symptoms, normal platelet function, and normal megakaryocyte count. Defects in GP1BA are the cause of pseudo-von Willebrand disease (VWDP) [MIM:177820]. A bleeding disorder is caused by an increased affinity of GP-Ib for soluble vWF resulting in impaired hemostatic function due to the removal of vWF from the circulation. 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. [GP1BA_HUMAN] GP-Ib, a surface membrane protein of platelets, participates in the formation of platelet plugs by binding to the A1 domain of vWF, which is already bound to the subendothelium. 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.

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