Imperial College London
Dr Tom McKinnon

Dr Tom McKinnon

Faculty of Medicine, Department of Immunology and Inflammation

Senior Lecturer in Immunology and Inflammation
 
 
 
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Contact

 

+44 (0)20 3313 2214t.mckinnon03

 
 
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Location

 

Commonwealth BuildingHammersmith Campus

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Summary

 

Publications

Citation

BibTex format

@article{Shiltagh:2014:10.1182/blood-2013-07-517086,
author = {Shiltagh, N and Kirkpatrick, J and Cabrita, LD and McKinnon, TAJ and Thalassinos, K and Tuddenham, EGD and Hansen, DF},
doi = {10.1182/blood-2013-07-517086},
journal = {Blood},
pages = {4143--4151},
title = {Solution structure of the major factor VIII binding region on von Willebrand factor},
url = {http://dx.doi.org/10.1182/blood-2013-07-517086},
volume = {123},
year = {2014}
}
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RIS format (EndNote, RefMan)

TY  - JOUR
AB  - 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.
AU  - Shiltagh,N
AU  - Kirkpatrick,J
AU  - Cabrita,LD
AU  - McKinnon,TAJ
AU  - Thalassinos,K
AU  - Tuddenham,EGD
AU  - Hansen,DF
DO  - 10.1182/blood-2013-07-517086
EP  - 4151
PY  - 2014///
SN  - 0006-4971
SP  - 4143
TI  - Solution structure of the major factor VIII binding region on von Willebrand factor
T2  - Blood
UR  - http://dx.doi.org/10.1182/blood-2013-07-517086
UR  - http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcApp=PARTNER_APP&SrcAuth=LinksAMR&KeyUT=WOS:000342618100019&DestLinkType=FullRecord&DestApp=ALL_WOS&UsrCustomerID=1ba7043ffcc86c417c072aa74d649202
UR  - https://ashpublications.org/blood/article/123/26/4143/32801/Solution-structure-of-the-major-factor-VIII
VL  - 123
ER  -
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