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

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.

journal_name

Blood

journal_title

Blood

authors

Shiltagh N,Kirkpatrick J,Cabrita LD,McKinnon TA,Thalassinos K,Tuddenham EG,Hansen DF

doi

10.1182/blood-2013-07-517086

subject

Has Abstract

pub_date

2014-06-26 00:00:00

pages

4143-51

issue

26

eissn

0006-4971

issn

1528-0020

pii

blood-2013-07-517086

journal_volume

123

pub_type

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