'Le charme discret’ of the Von Willebrand factor - factor VIII complex
PhD thesis defense Malgorzata Przeradzka News
On 26 October 2020 Malgorzata Przeradzka will defend her PhD thesis ‘Le charme discret’ of the Von Willebrand factor - factor VIII complex at Utrecht University. Her thesis addresses the interaction between VWF and FVIII as well as the cellular uptake mechanism of VWF. The results described in this thesis contribute to our understanding of bleeding disorders that are related to defects in FVIII-VWF complex formation.
the coagulation proteins Von Willebrand Factor (VWF) and Factor VIII (FVIII) are key players in the molecular mechanisms behind bleeding arrest at sites of vascular injury. VWF also acts as a carrier protein for FVIII and has a dual role in regulating the FVIII half-life in vivo. On the one hand, VWF mediates the catabolism of FVIII via poorly understood cellular mechanisms. On the other hand, VWF protects FVIII from fast clearance from the circulation.
To analyse the protein complex of FVIII and VWF, protein chemical footprinting techniques combined with mass spectrometry were employed. Studying changes in solvent accessibility of amino acid residues with reversible and irreversible labelling methods allowed us to understand the architecture and dynamics of the FVIII-binding region of VWF.
The comparison of the C1 domains structures of FVIII and Factor V (which does not bind VWF) revealed a unique presence of surface exposed hydrophobic residues in the FVIII C1 domain. This allowed us to identify additional residues on FVIII that are essential for VWF binding. Using cellular uptake studies, we have also obtained evidence that low density lipoprotein receptor-related protein and macrophage scavenger receptor cooperate in the endocytosis of VWF.
Promotores: prof AB Meijer PhD and prof K Mertens PhD
Copromotor: M van den Biggelaar PhD
Location: Utrecht University, Academy Building
