Schematic representation of the A1-A2-B-A3-C1-C2 domain organization of human fV (2196 residues) and its derivatives, fVa (1360 residues) and fVai (957 residues). The number of residues in each domain is indicated, along with relevant sites of cleavage by thrombin (R709, R1018, and R1545) and APC (R306 and R506). Removal of the large B domain (836 residues) by thrombin produces the fVa heterodimer composed of heavy (A1-A2) and light (A3-C1-C2) chains containing 709 and 651 residues, respectively. Further cleavage by APC at R306 and R506 produces fVai. The X-ray structure of bovine fVai was reported previously.³¹  This structure contains no information on the sites of cleavage in the A2 and B domains and also carries disorder in the A1 domain around R306. The cryo-EM structures of human fV and fVa are reported in this study (Figure 2). The structure of fV contains all residues of the A1-A2-A3-C1-C2 assembly and 14 additional residues in the B domain.