Structural and functional characterization of protein complexes in the blood coagulation cascade

Jesper Jonasson Madsen

Research output: Book/ReportPh.D. thesis

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Abstract

In this dissertation, components of coagulation factor (F)X-activating (tenase; fXase) complexes are studied using computational biophysics and the molecular dynamics (MD) method. The main focus is on structure-function relationships of the two central tenase complexes with respect to activation processes, complex formation, and platelet membrane association. Both the intrinsic and the extrinsic tenase complex consists of a trypsin-like serine protease and auxiliary domains complexed with the appropriate cofactor; FIXa with FVIIIa and FVIIa with tissue factor (TF), respectively. Topics covered will include the structural and dynamical changes upon proteolytic activation and TF-induced allosteric activation of FVIIa. In addition, FVIIa variants with the 170-loop grafted from trypsin will be looked into and, in particular, the mechanisms that enable these variants to have increased activity without TF are explained. Furthermore, the inter-domain linker connecting the two epidermal growth factor-like domains of FVIIa will be discussed with respect to consequences for its ability to form a productive complex with tissue factor. Finally, membrane binding of FVIIIa as mediated by the tandem C2-like domains is described using a highly mobile membrane-mimetic model.
Original languageEnglish
PublisherDTU Chemistry
Number of pages235
Publication statusPublished - 2014

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