3ppy
From Proteopedia
Crystal structure of the D1596A/N1602A double mutant of an engineered VWF A2 domain (N1493C and C1670S)
Structural highlights
DiseaseVWF_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. FunctionVWF_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 proteolysis of VWF by ADAMTS13 is an essential step in the regulation of its hemostatic and thrombogenic potential. The cleavage occurs at strand beta4 in the structural core of the A2 domain of VWF, so unfolding of the A2 domain is a prerequisite for cleavage. In the present study, we present the crystal structure of an engineered A2 domain that exhibits a significant difference in the alpha3-beta4 loop compared with the previously reported structure of wild-type A2. Intriguingly, a metal ion was detected at a site formed mainly by the C-terminal region of the alpha3-beta4 loop that was later identified as Ca(2+) after various biophysical and biochemical studies. Force-probe molecular dynamic simulations of a modeled structure of the wild-type A2 featuring the discovered Ca(2+)-binding site revealed that an increase in force was needed to unfold strand beta4 when Ca(2+) was bound. Cleavage assays consistently demonstrated that Ca(2+) binding stabilized the A2 domain and impeded its unfolding, and consequently protected it from cleavage by ADAMTS13. We have revealed a novel Ca(2+)-binding site at the A2 domain of VWF and demonstrated a relationship between Ca(2+) and force in the regulation of VWF and primary hemostasis. A novel calcium-binding site of von Willebrand factor A2 domain regulates its cleavage by ADAMTS13.,Zhou M, Dong X, Baldauf C, Chen H, Zhou Y, Springer TA, Luo X, Zhong C, Grater F, Ding J Blood. 2011 Apr 28;117(17):4623-31. Epub 2011 Mar 8. PMID:21385852[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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Categories: Homo sapiens | Large Structures | Ding J | Dong X | Zhong C | Zhou M
