Factor XII Explored with AlphaFold - Opportunities for Selective Drug Development

Author:

Frunt Rowan1,El Otmani Hinde1,Gibril Kaira Bubacarr1,de Maat Steven1,Maas Coen1

Affiliation:

1. CDL Research, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands

Abstract

AbstractMedical 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.

Funder

Trombosestichting Nederland

Publisher

Georg Thieme Verlag KG

Subject

Hematology

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Cited by 3 articles. 订阅此论文施引文献 订阅此论文施引文献,注册后可以免费订阅5篇论文的施引文献,订阅后可以查看论文全部施引文献

1. Factor XII Structure–Function Relationships;Seminars in Thrombosis and Hemostasis;2023-06-05

2. Editorial: Kinin 2022 Meeting, Annecy, France;Journal of Clinical Medicine;2023-05-04

3. Taking aim at titanium;Journal of Thrombosis and Haemostasis;2023-05

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