6n29
From Proteopedia
Crystal structure of monomeric von Willebrand Factor D`D3 assembly
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 PubMedD assemblies comprise half of von Willebrand factor yet are of unknown structure. D1 and D2 in the prodomain and D'D3 in mature VWF at Golgi pH form helical VWF tubules in Weibel Palade bodies and template dimerization of D3 through disulfides to form ultralong VWF concatemers. D'D3 forms the binding site for factor VIII. The crystal structure of monomeric D'D3 with cysteine residues required for dimerization mutated to alanine was determined at endoplasmic reticulum (ER)-like pH. The smaller C8-3, TIL3 and E3 modules pack through specific interfaces as they wind around the larger, N-terminal, Ca(2+)-binding VWD3 module to form a wedge shape. D' with its TIL' and E' modules projects away from D3. The two mutated cysteines implicated in D3 dimerization are buried, providing a mechanism for protecting them against premature disulfide linkage in the ER where intrachain disulfide linkages are formed. D3 dimerization requires co-association with D1 and D2, Ca(2+), and Golgi-like acidic pH. Associated structural rearrangements in the C8-3 and TIL3 modules are required to expose cysteine residues for disulfide linkage. Our structure provides insight into many von Willebrand disease mutations including those that diminish FVIII binding, which suggest that factor VIII binds not only to the N-terminal TIL' domain of D' distal from D3 but also extends across one side of D3. The organizing principle for the D3 assembly has implications for other D assemblies and the construction of higher order, disulfide-linked assemblies in the Golgi in both VWF and mucins. The von Willebrand factor D'D3 assembly and structural principles for factor VIII binding and concatemer biogenesis.,Dong X, Leksa NC, Chhabra ES, Arndt JW, Lu Q, Knockenhauer KE, Peters RT, Springer TA Blood. 2019 Jan 14. pii: blood-2018-10-876300. doi: 10.1182/blood-2018-10-876300. PMID:30642920[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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