4nt5 | pdb_00004nt5
Crystal structure of human von Willebrand factor CTCK domain
Structural highlights
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.[1] [2] 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 PubMedThe C-terminal cystine knot (CK) (CTCK) domain in von Willebrand factor (VWF) mediates dimerization of proVWF in the endoplasmic reticulum and is essential for long multimers required for hemostatic function. The CTCK dimer crystal structure reveals highly elongated monomers with 2 beta-ribbons and 4 intra-chain disulfides, including 3 in the CK. Dimerization buries an extensive interface of 1500 A(2) corresponding to 32% of the surface of each monomer and forms a super beta-sheet and 3 inter-chain disulfides. The shape, dimensions, and N-terminal connections of the crystal structure agree perfectly with previous electron microscopic images of VWF dimeric bouquets with the CTCK dimer forming a down-curved base. The dimer interface is suited to resist hydrodynamic force and disulfide reduction. CKs in each monomer flank the 3 inter-chain disulfides, and their presence in beta-structures with dense backbone hydrogen bonds creates a rigid, highly crosslinked interface. The structure reveals the basis for von Willebrand disease phenotypes and the fold and disulfide linkages for CTCK domains in diverse protein families involved in barrier function, eye and inner ear development, insect coagulation and innate immunity, axon guidance, and signaling in extracellular matrices. Highly reinforced structure of a C-terminal dimerization domain in von Willebrand factor.,Zhou YF, Springer TA Blood. 2014 Mar 20;123(12):1785-93. doi: 10.1182/blood-2013-11-523639. Epub 2014 , Jan 6. PMID:24394662[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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