2MHQ

Solution structure of the major factor VIII binding region on von Willebrand factor

Summary for 2MHQ

• Entry DOI: 10.2210/pdb2mhq/pdb
• Related: 2MHP
• Descriptor: von Willebrand factor (1 entity in total)
• Functional Keywords: von willebrand factor, factor viii, ensemble refinement, blood clotting
• Biological source: Homo sapiens (human)
• Cellular location: Secreted: P04275
• Total number of polymer chains: 1
• Total formula weight: 11351.28

Authors

Shiltagh, N.,Kirkpatrick, J.,Cabrita, L.D.,McKinnon, T.A.J.,Thalassinos, K.,Tuddenham, E.G.D.,Hansen, D.F. (deposition date: 2013-12-02, release date: 2014-05-14, Last modification date: 2024-10-30)

Primary citation

Shiltagh, N.,Kirkpatrick, J.,Cabrita, L.D.,McKinnon, T.A.,Thalassinos, K.,Tuddenham, E.G.,Hansen, D.F.
Solution structure of the major factor VIII binding region on von Willebrand factor.
Blood, 123:4143-4151, 2014

PubMed Abstract: Although 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 2 domains, trypsin-inhibitor-like (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 β 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.

PubMed: 24700780
DOI: 10.1182/blood-2013-07-517086

Experimental method

SOLUTION NMR