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Thromb Haemost 2023; 123(02): 177-185
DOI: 10.1055/a-1951-1777
Review Article

Factor XII Explored with AlphaFold - Opportunities for Selective Drug Development

Rowan Frunt
1   CDL Research, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands
,
Hinde El Otmani
1   CDL Research, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands
,
Bubacarr Gibril Kaira
1   CDL Research, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands
,
Steven de Maat
1   CDL Research, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands
,
Coen Maas
1   CDL Research, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands
› Author Affiliations Funding This study was supported by Trombosestichting Nederland (2020_1).
› Further Information
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Abstract

Medical device associated thrombosis is an important clinical problem. This type of thrombosis can result from Factor XII (FXII) binding to non-natural surface materials and subsequent activation of the contact pathway. This drives the development of new therapeutic strategies to block this pathway and information on the structural properties of FXII should catalyse this quest. Presently, there is no publicly available crystal structure of full-length FXII. However, the AlphaFold Protein Structure Database provides a model structure. We here explore this model in combination with previous structure-function studies to identify opportunities for selective pharmacological blockade of the contribution of FXII in medical device associated thrombosis. Previous studies demonstrated that FXII activation is dependent on molecular cleavage after R353. We subsequently proposed that protein conformation protects this cleavage site to ensure zymogen quiescence and prevent inappropriate FXII activation. The AlphaFold model shows that a small loop containing R353 indeed is buried in the globular molecule. This is the result of intra-molecular interactions between the (N-terminal) Fibronectin type II domain, (central) kringle and (C-terminal) protease domain, in a structure that resembles a three-point harness. Furthermore, this interaction pushes the intermediate domains, as well as the flexible proline-rich region (PRR), outward while encapsulating R353 in the molecule. The outward directed positively charged patches are likely to be involved in binding to anionic surfaces. The binding of FXII to surfaces (and several monoclonal antibodies) acccelerates its activation by inducing conformational changes. For prevention of medical device associated thrombosis, it is therefore important to target the surface binding sites of FXII without causing structural changes.

Keywords

thrombosis - factor XII - AlphaFold


Publication History

Received: 13 June 2022

Accepted: 27 September 2022

Accepted Manuscript online:
27 September 2022

Article published online:
15 December 2022

© 2022. Thieme. All rights reserved.

Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany

 

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