View source for 2mhq


==Solution structure of the major factor VIII binding region on von Willebrand factor==
<StructureSection load='2mhq' size='340' side='right'caption='[[2mhq]]' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[2mhq]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full experimental information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2MHQ OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2MHQ FirstGlance]. <br>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">Solution NMR, 10 models</td></tr>
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=2mhq FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2mhq OCA], [https://pdbe.org/2mhq PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2mhq RCSB], [https://www.ebi.ac.uk/pdbsum/2mhq PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2mhq ProSAT]</span></td></tr>
</table>
== Disease ==
[https://www.uniprot.org/uniprot/VWF_HUMAN VWF_HUMAN] Defects in VWF are the cause of von Willebrand disease type 1 (VWD1) [MIM:[https://omim.org/entry/193400 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.<ref>PMID:10887119</ref> <ref>PMID:11698279</ref>   Defects in VWF are the cause of von Willebrand disease type 2 (VWD2) [MIM:[https://omim.org/entry/613554 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:[https://omim.org/entry/277480 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 ==
[https://www.uniprot.org/uniprot/VWF_HUMAN 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.
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
While much of the function of von Willebrand factor (VWF) has been revealed, detailed insight into the molecular structure that enables VWF to orchestrate hemostatic processes, in particular factor VIII (FVIII) binding and stabilization in plasma, is lacking. Here we present the high-resolution solution structure and structural dynamics of the D' region of VWF, which constitutes the major FVIII binding site. D' consists of two domains, TIL' and E', of which the TIL' domain lacks extensive secondary structure, is strikingly dynamic and harbors a cluster of pathological mutations leading to decreased FVIII binding affinity (type 2N von Willebrand disease (VWD)). This indicates that the backbone malleability of TIL' is important for its biological activity. The principal FVIII binding site is localized to a flexible, positively charged region on TIL', which is supported by the rigid scaffold of the TIL' and E' domain beta-sheets. Furthermore, surface-charge mapping of the TIL'E' structure reveals a potential mechanism for the electrostatically guided, high-affinity VWF.FVIII interaction. Our findings provide novel insights into VWF.FVIII complex formation, leading to a greater understanding of the molecular basis of the bleeding diathesis type 2N VWD.

Solution structure of the major factor VIII binding region on von Willebrand factor.,Shiltagh N, Kirkpatrick J, Cabrita LD, McKinnon TA, Thalassinos K, Tuddenham EG, Hansen DF Blood. 2014 Apr 3. PMID:24700780<ref>PMID:24700780</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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<div class="pdbe-citations 2mhq" style="background-color:#fffaf0;"></div>
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Cabrita LD]]
[[Category: Hansen DF]]
[[Category: Kirkpatrick J]]
[[Category: McKinnon TAJ]]
[[Category: Shiltagh N]]
[[Category: Thalassinos K]]
[[Category: Tuddenham EGD]]