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Thromb Haemost 2018; 118(01): 028-041
DOI: 10.1160/TH17-06-0404
Review Article
Schattauer GmbH Stuttgart

Insights into 3D Structure of ADAMTS13: A Stepping Stone towards Novel Therapeutic Treatment of Thrombotic Thrombocytopenic Purpura

Bogac Ercig   *
,
Kanin Wichapong
,
Chris P. M. Reutelingsperger   *
,
Karen Vanhoorelbeke   *
,
Jan Voorberg   *
,
Gerry A.F. Nicolaes   *
Further Information

Publication History

12 June 2017

13 October 2017

Publication Date:
05 January 2018 (online)

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Abstract

ADAMTS13 (a disintegrin and metalloprotease with a thrombospondin type-1 motif, member 13) and von Willebrand factor (VWF) can be considered as scale weights which control platelet adhesion during primary haemostasis. In a very uncommon condition designated thrombotic thrombocytopenic purpura (TTP), functional absence of ADAMTS13 tips the balance toward VWF-mediated platelet adhesion in the microcirculation. TTP is associated with a high mortality and arises from either a congenital or acquired autoimmune deficiency of the plasma enzyme ADAMTS13. In case of acquired ADAMTS13 deficiency, autoantibodies bind to and inhibit the function of ADAMTS13. Currently available treatments of TTP aim to supply ADAMTS13 through plasma exchange or are aimed at B-cell depletion with rituximab. None of the available therapeutics, however, aims at protection of ADAMTS13 from circulating autoantibodies. In this review, our aim is to describe the structure–function relationship of ADAMTS13 employing homology models and previously published crystal structures. Structural bioinformatics investigation of ADAMTS13 reveals many insights and explains how mutations and autoantibodies may lead to the pathophysiology of TTP. The results of these studies provide a roadmap for the further development of rationally designed therapeutics for the treatment of patients with acquired TTP. In addition, we share our opinion on the state of the art of the open–closed conformations of ADAMTS13 which regulate the activity of this highly specific VWF cleaving protease.

Keywords

ADAMTS13 - von Willebrand factor - thrombosis - thrombotic thrombocytopenic purpura - autoimmune diseases

* On behalf of the PROFILE Consortium, http://www.itn-profile.eu/


 

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