Thesis defense Awital Bar Barroeta
Novel insights into structure and function of Factor XI
On 24 March 2023 (16:00 hrs) Sanquin researcher Awital Bar Barroeta expects to defend her PhD thesis 'Novel insights into structure and function of Factor XI' at the University of Amsterdam.
Promotores
Prof JCM Meijers PhD
Prof AB Meijer PhD
Venue
Agnietenkapel, Universiteit van Amsterdam and online
Summary
Factor XI (FXI) is a protein in the coagulation cascade. After activation by either factor XIIa (FXIIa) in the intrinsic pathway or by thrombin, activated FXI (FXIa) activates FIX to promote coagulation. FXI provides a supportive role in haemostasis, promoting thrombin generation to ensure fibrin clot integrity and prevent clot degradation. Nevertheless, increased levels of FXI are a risk factor for thrombosis. It has been hypothesised that the prothrombotic role of FXI is associated with its activation by FXIIa, while feedback activation of FXI by thrombin is thought to maintain clot stability in haemostasis. In this thesis we have tried to further explore the structure of FXI and its interactions with proteins to better understand structure-function relationships of FXI and how these relate to FXI function in haemostasis and thrombosis. In this thesis we used hydrogen-deuterium exchange- and crosslinking-mass spectrometry to specify the binding site of HK and FIX on FXI as well as to elucidate conformational changes related to FXI activation. Moreover, the thesis describes the development of a variety of nanobodies against FXI that can be used as tool compounds for the investigation of FXI function. The thesis also reports a time-resolved fluorescence resonance energy transfer (TR-FRET) assay developed to quantify binding between FXI and thrombin-S205A for screening of small molecules with the ability to influence the FXI-thrombin interaction. Together, these findings may aid the development of novel therapeutics regulating FXI function.
