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

Shiltagh, N; (2013) Solution structure of the factor VIII binding region on von Willebrand factor. Doctoral thesis , UCL (University College London). Green open access

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Abstract

The preservation of haemostatic integrity is secured by the activities of von Willebrand factor (VWF). Upon vascular damage, VWF acts as a molecular bridge facilitating the initial adhesion and aggregation of platelets to the site of vessel injury, and consequently thrombus formation ensues. Furthermore, VWF is the faithful carrier of procoagulant factor VIII in plasma, thereby prolonging its half-life, and efficiently localising FVIII to the incipient platelet plug. The arrest of bleeding and maintenance of blood volume constancy is critically dependant on VWF; as is exemplified by von Willebrand disease (VWD) — the most common inherited bleeding disorder in man, resulting from defective or deficient VWF protein. Much of the function of VWF has been revealed, however, detailed insight into the molecular structure that enables VWF to orchestrate haemostatic processes, in particular FVIII stabilisation in plasma, is lacking. The high resolution NMR structure of the major FVIII binding region (D') on VWF, and the dynamics and flexibility of its substructure, are presented in this thesis. The complex disulphide-bonded D' region is composed of a two subdomain architecture — TIL'E'. Domain TIL' lacks extensive secondary structure, is strikingly dynamic on at least two timescales measured by NMR relaxation experiments, and this region is coincident with the clustering of pathological mutations leading to decreased FVIII binding affinity (type 2N VWD). This indicates that the conformational fluctuations and backbone malleability of domain TIL' collocate with biological activity. In contrast, the structured domain E', is rigid and contains the most commonly occurring and clinically mildest type 2N VWD mutation. These findings provide important insights into VWF:FVIII complex formation and represent a first step towards revealing the molecular basis of the bleeding diathesis type 2N von Willebrand disease.

Type: Thesis (Doctoral)
Title: Solution structure of the factor VIII binding region on von Willebrand factor
Open access status: An open access version is available from UCL Discovery
Language: English
UCL classification: UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Institute of Prion Diseases
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Institute of Prion Diseases > MRC Prion Unit at UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences > Structural and Molecular Biology
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute > Research Department of Haematology
URI: http://discovery.ucl.ac.uk/id/eprint/1419152
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