Structural architecture of the acidic region of the B domain of coagulation factor V

Abstract

BackgroundCoagulation factor (F)V features an A1-A2-B-A3-C1-C2 domain organization and functions as the inactive precursor of FVa, a component of the prothrombinase complex required for rapid thrombin generation in the penultimate step of the coagulation cascade. An intramolecular interaction within the large B domain (residues 710-1545) involves the basic region (BR, residues 963-1008) and acidic region (AR, residues 1493-1537) and locks FV in its inactive state. However, structural information on this important regulatory interaction or on the separate architecture of the AR and BR remains elusive due to conformational disorder of the B domain. ObjectivesTo reveal the structure of the BR-AR interaction or of its separate components. MethodsThe structure of FV is solved by cryogenic electron microscopy. ResultsA new 3.05 Å resolution cryogenic electron microscopy structure of FV confirms the overall organization of the A and C domains but resolves the segment 1507 to 1545 within a largely disordered B domain. The segment contains most of the AR and is organized as recently reported in FV short, a spliced variant of FV with a significantly shorter and less disordered B domain. ConclusionThe similar architecture of the AR in FV and FV short provides structural context for physiologically important interactions of this region with the BR in FV and with the basic C-terminal end of tissue factor pathway inhibitor α in FV short.