Cryo-EM structures of FV and FVa. The domains of both proteins are shown in wheat (A1), pale green (A2), light blue (B), pale yellow (A3), light pink (C1), and pale cyan (C2). The FV/FVa C domains provide a platform supporting the A domains. The A1 and A3 domains sit on top of the C domains, with the A2 domain resting between the A1 and A3 domains and having no contact with the C domains. The A1-A2-A3-C1-C2 domain assembly is resolved, whereas the B domain is more dynamic and only visible at the most N- and C-terminal segments, directly connected with the A2 and A3 domains, respectively. The sites of thrombin activation at Arg709 and Arg1545 (magenta) are clearly visible in the FV structure. The sites of APC cleavage at Arg306 and Arg506 are largely buried in FV but become more exposed after thrombin-mediated activation (please compare FV and FVa structures), priming FVa for APC-mediated inactivation. The spikes in the C domains responsible for membrane binding are shown in olive, and the FXa- and APC-binding epitopes are shown in orange and blue, respectively. Amino acid residues are highlighted using their 1-letter codes. The figure has been adapted from Figure 2B,E in the article by Ruben et al that begins on page 3137.